JPH09255664A - New bone-resorption inhibitor and antagonist for vitronectin receptor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound useful as a bone resorption inhibiting agent, an agent for inhibiting growth and metastasis of tumor, an anti- inflammatory agent, an antagonist for vitronectin receptor, etc.

SOLUTION: This compound is expressed by formula I [W is R¹-A-B-D-C(R¹⁶), etc., (R¹ is R²-C(=NR²)NR², etc.; R² is H, etc.; A is a single direct bond, a (1-8C)-alkanediyl, etc.; B is a single direct bond, a (5-10C)-arylene, etc.; D is a single direct bond, NR², etc.; R¹⁶ is H, etc.); Y is C=O, CH₂, etc.; Z is N(R⁰), O, etc.; R⁰ is H, etc.; E is a single direct bond, a (1-8C)-alkanediyl, etc.; F is same as D; G is group of formula II (R⁴ to R⁷ are each H, F, OH, etc.; R¹⁰ is C(O)R¹¹, etc.; R¹¹ is OH, etc.; (p) and (q) are each 0 or 1)] and its salt, e.g. (2S)-benzoylcarbonylamino-3-[2-((4S)-(3-(4,5-dihydro-1H-imidazol-2-ylamino) propyl)-2,5-dioxoimidazolidin-1-yl)acetylamino]propionic acid.

COPYRIGHT: (C)1997,JPO

Description

Detailed Description of the Invention

The present invention relates to compounds of the formula I and physiologically acceptable salts of these compounds, pharmaceutical preparations containing these compounds, processes for preparing these compounds and, in particular, as osteoclasts, as osteoclasts. Bone reabs
for the treatment or prevention of cardiovascular diseases such as atherosclerosis or restenosis, as inhibitors of tumor growth and metastasis, as inhibitors of tumor growth and metastasis, and nephropathy and Vitronectin receptor for treating or preventing retinopathy, for example diabetic retinopathy, and also for treating and preventing diseases based on interactions between vitronectin receptors and their ligands in cell-cell or cell-matrix interaction processes It relates to the use of these compounds as body antagonists. Furthermore, the present invention provides compounds of formula I and their compounds as medicaments for reducing or treating diseases associated with at least partially undesired degrees of bone resorption, angiogenesis or proliferation of cells of the smooth vascular musculature. It relates to the use of physiologically acceptable salts and pharmaceutical preparations containing these compounds.

Human bone undergoes a continuous dynamic process of remodeling, which involves bone resorption and bone synthesis. These processes are controlled by the type of cell that is specific for this purpose. Bone synthesis is based on the deposition of bone matrix by osteoblasts, and bone resorption is based on the destruction of bone matrix by osteoclasts. The majority of bone disorders are due to an impaired balance between bone formation and bone resorption. Osteoporosis is
Characterized by loss of bone matrix. Activated osteoclasts are multinucleated cells with diameters up to 400 μm that destroy the bone matrix. Activated osteoclasts themselves adhere to the surface of the bone matrix and secrete proteolytic enzymes and acids in the so-called sealing zone, the area between the cell membrane and the bone matrix. . The acidic environment and proteases cause bone destruction.

The novel compounds of formula I inhibit bone resorption by osteoclasts. Bone diseases in which this novel compound can be used include periarticular erosion and paget in osteoporosis, hypercalcemia, especially osteopenia induced by metastasis, tooth disease, hyperparathyroidism, rheumatoid arthritis, among others. I have a disease. Furthermore, the compounds of formula I can be used for the alleviation, avoidance or treatment of bone disorders caused by glucocorticoid treatment, steroid treatment or corticosteroid treatment or due to deficiency of sex hormones. All these diseases are characterized by bone loss due to an imbalance between bone synthesis and bone destruction. Studies demonstrate that osteoclast adhesion to bone is regulated by integrin receptors on the cell surface of osteoclasts.

Integrins are a superfamily of receptors which include, among others, the fibrinogen receptor α _IIb β ₃ on platelets and the vitronectin receptor α _V β ₃ .
The vitronectin receptor α _v β ₃ is a membrane glycoprotein expressed on the cell surface of many cells such as endothelial cells, smooth vascular muscular cells, osteoclasts and tumor cells. The α _V β ₃ vitronectin receptor expressed on the osteoclast membrane regulates the processes of adhesion and resorption to bone and is responsible for osteoporosis. In this connection, α _V β ₃ is
It binds to bone matrix proteins such as osteopontin, bone sialoprotein and thrombospondin containing the tripeptide motif Arg-Gly-Asp (or RGD).

Horton and coworkers have described an RGD peptide and an anti-vitronectin receptor (23C6) that inhibits osteoclasts and tooth destruction by migration of osteoclasts (Horton et al., Exp. Cell. Res. .1991, 195, 36
8). In J. Cell Biol. 1990, 111, 1713, Sato et al., An RGD peptide from snake venom, echistatin, is a potent inhibitor of bone resorption in tissue culture and an inhibitor of osteoclast adhesion to bone. Have reported that. Fischer et al. (Endocrinology, 1993, 132, 1411)
Could illuminate that in rats, ethistatin also inhibits bone resorption in vivo.

Α on human cells of the smooth vascular musculature of the aorta
_V beta ₃ vitronectin receptor stimulates the migration of these cells into the neointima (neointima). This process ultimately leads to post-angioplasty atherosclerosis and restenosis (Brown et al., Cardiovascular Res. 1994, 28, 1
815). Furthermore, the compounds of formula I can be used as carriers for agents which are effective in the treatment of the abovementioned diseases, thus allowing the agents to be specifically transferred to the desired target (= drug targeted transport, eg. Targeted Drug Delivery,
RC Juliano, Handbookof Experimental Pharmacolog
y, Vol. 100, Ed. Born, GVR et al, Springer Verl
See ag).

Brooks et al. (Cell 1994, 79, 1157) reported that α _V
It has been demonstrated that antibodies to β ₃ or α _v β ₃ antagonists can shrink tumors by inducing apoptosis of vascular cells during angiogenesis. Ch
ersh et al. (Science 1995, 270, 1500), an anti-alpha that inhibits the bFGF-induced angiogenic process in rat eyes.
_V β ₃ antibodies or α _V β ₃ antagonists have been described.
Some of these substances have therapeutic value in the treatment of retinopathy.

EP-A 449 079, EP-A 53
0 505, EP-A 566 919 and WO 93 /
18057 describes hydantoin derivatives and WO
95/14008 describes substituted 5-membered heterocyclic compounds, both groups of these compounds exhibiting platelet aggregation-inhibitory action. Patent application WO 94/12181
Describes aromatic or non-aromatic ring systems and WO 9
4/08577 describes substituted heterocyclic compounds, both groups of these compounds acting as fibrinogen receptor antagonists and inhibitors of platelet aggregation. EP-A-528 586 and EP-A-528
587 describes aminoalkyl-substituted or heterocyclyl-substituted phenylalanine derivatives and WO 9
5/32710 describes aryl derivatives, a group of all these compounds acting as inhibitors of bone resorption by osteoclasts. WO95 / 28426 RG acts as an inhibitor of bone resorption, angiogenesis and restenosis
The D peptide is described. WO 96/00574
Describes benzodiazepines and WO 96/00
730 describes fibrinogen receptor antagonist templates, especially benzodiazepines linked to a nitrogen-containing 5-membered ring, both groups of compounds acting as vitronectin receptor antagonists.

The present invention provides the formula I

Embedded image And a physiologically acceptable salt thereof.

In the above formula, W is R ¹ -A-B-D
-C (R ¹⁶ ), R ¹ -A-B-D-C (R ¹⁶ ) = C,

Embedded image [Wherein the ring system

Embedded image Is one or more saturated or unsaturated containing 1 or 2 heteroatoms from the group N, O and S and substituted by 1 to 3 substituents from R ^16. Y or substituted with one or two doubly bonded O or S]; Y
Is, C = O, C = S or -CH ₂ -; Z is, N
(R ⁰ ), O, S or —CH ₂ —; A is a single direct bond, (C ₁ -C ₈ ) -alkanediyl, —NR ² —N
^{= CR 2 -, - NR 2} -C (O) -NR 2 -, - NR 2 -C
(O) O -, - NR 2 -C (O) S -, - NR 2 -C (S) -N
^{R 2 -, - NR 2 -C} (S) -O -, - NR 2 -C (S) -S
^{-, - NR 2 -S (O} ) n -NR 2 -, - NR 2 -S (O) n -
^{O -, - NR 2 -S (} O) n -, (C 3 -C 12) - ^{cycloalkanediyl, -C≡C -, - NR 2 -C} (O) -, - C
^{(O) -NR 2 -, -} (C 5 -C 14) - arylene -C (O) -
^{NR 2 -, - O -,} - S (O) n -, (C 5 -C 14) - arylene -, - CO -, (C 5 -C 14) - arylene -CO
^{-, - NR 2 -, -} SO 2 -NR 2 -, - C (O) O -, -
O-C (O) -, - N = CR 2 -, - R 2 C = N -, - CR
² = CR ³ - or - (C ₅ -C ₁₄₎ - arylene -S (O) _n
-[These groups may in each case be substituted by NR ² and / or-(C ₁ -C
₈₎ - alkanediyl _{^{-CO-NR 2 - (C 1}} -C 8) - alkanediyl, - (C ₁ -C ₈₎ - alkanediyl -CO-N
R ² — or —CO—NR ² — (C ₁ -C ₈ ) -alkanediyl optionally substituted by ₁ or 2 (C ₁ -C ₈ ) -alkanediyl]; B is a single direct bond, (C ₁ -C ₈ ) -alkanediyl, (C ₅ -C
₁₀₎ - arylene, (C ₃ -C ₈₎ - cycloalkyl ^{alkanediyl, -C≡C -, - NR 2 -} , - C (O) -, NR 2 -C
(O) -, - C ( O) -NR 2 -, - NR 2 -C (O) -N
^{R 2, -NR 2 -C (S} ) -NR 2 -, - OC (O) -, - C
(O) O -, - S (O) -, - S (O) 2 -, - S (O) -NR 2
_{-, - S (O) 2} -NR 2 -, - NR 2 -S (O) -, - NR 2
_{-S (O) 2 -, -} O -, - S- , or -CR ² = CR ³ -
[These radicals are in each case

[0011]

Embedded image Or ^{_{- (CH 2) 2 -NR 2}} -C (O) - 1 or 2 as (C ₁ -C ₈₎ - an alkane which may be substituted by diyl] or 1 or 2 5- or 6-membered saturated or unsaturated containing one nitrogen atom and optionally substituted by one or two (C ₁ -C ₆ ) -alkyl or double-bonded oxygen or sulfur 2 of the ring
Is a valent group; D is a single direct bond, (C ₁ -C ₈ )-
Alkanediyl, (C ₅ -C ₁₀₎ - arylene, -O-,
^{-NR 2 -, - CO-NR} 2 -, - NR 2 -CO -, - N
^{R 2 -C (O) -NR 2} -, - NR 2 -C (S) -NR 2 -, -
OC (O)-, -C (O) O-, -CO-, -CS-, -S
(O) -, - S ( O) 2 -, - S (O) 2 -NR 2 -, - NR 2 -
S (O) -, - NR 2 -S (O) 2 -, - S -, - CR 2 = C
^{R 3 -, - C≡C -,} - NR 2 -N = CR 2 -, - N = C
R ² , —R ² C═N— or —CH (OH) — [these radicals are in each case

[0012]

Embedded image - phenylene -NR ² -C (O) - or - (CH _{2) 2} -S
One or two (C ₁ -C ₈ )-, such as (O) ₂ —CH ₂ —
Alkanediyl, -CR ² = CR ³ - or (C ₅ -C ₆₎ -
Optionally substituted by arylene]; E
Is a single direct bond, (C ₁ -C ₆ ) -alkanediyl,
(C ₂ -C ₆₎ - alkenediyl, (C ₂ -C ₆₎ - alkynediyl, phenylene, phenylene - (C ₁ -C ₃₎ - alkanediyl or (C ₁ -C ₃₎ - be a phenylene - alkanediyl; F is as defined as D; G is

[0013]

Embedded image L is C (R ¹⁶ ) or N; R ⁰ is H,
(C ₁ -C ₈ ) -Alkyl, optionally substituted by one or more than one fluorine, (C _3- )
C ₁₂₎ - cycloalkyl, (C ₃ -C ₁₂₎ - cycloalkyl - (C ₁ -C ₈₎ - alkyl, (C ₅ -C ₁₄₎ - aryl, (C
_5- C ₁₄ ) -aryl- (C ₁ -C ₈ ) -alkyl, (C ₁ -C)
₈₎ - alkyl -C (O) -, (C 3 -C 12) - cycloalkyl _{-C (O), (C 3} -C 12) - cycloalkyl - (C ₁ -
C ₆₎ - alkyl _{-C (O), (C 5} -C 14) - aryl -C
(O)-or (C ₅ -C ₁₄ ) -Aryl- (C ₁ -C ₆ ) -alkyl-C (O) [The alkyl group can be substituted by one or more than one fluorine ] And R ^{1
Is, R 2 -C (= NR 2} ) NR 2 -, R 2 R 3 N-C (= NR 2)
^{-, R 2 R 3 N-} C - (= NR 2) -NR 2 or N as the case, by the well and if also contain 1 to 4 heteroatoms selected from the group of O and S Is a 4- to 14-membered monocyclic or polycyclic aromatic group optionally substituted by one or more substituents from the group of R ¹² , R ¹³ , R ¹⁴ and R ^15. A non-aromatic ring system; R ² and R ³ , independently of each other, are optionally substituted with H, optionally one or more than _one (C ₁ -C ₁₀ )- alkyl, (C ₃ -C ₁₂₎ - cycloalkyl, (C ₃ -C ₁₂₎ - cycloalkyl - (C ₁ -C ₈₎
- alkyl, (C ₅ -C ₁₄₎ - aryl, (C ₅ -C ₁₄₎ - aryl - (C ₁ -C ₈₎ - ^{_{alkyl, H 2 N, R 8 ONR}} 9,
^{R 8 OR 9, R 8 OC} (O) R 9, R 8 - (C 5 -C 14) - aryl ^{-R 9, R 8 R 8 NR} 9, HO- (C 1 -C 8) - alkyl -
NR ⁸ R ⁹ , R ⁸ R ⁸ NC (O) R ⁹ , R ⁸ C (O) NR ⁸ R ⁹ , R
⁸ C (O) R ⁹ , R ⁸ R ⁸ NC (= NR ⁸ )-, R ⁸ R ⁸ NC
(= NR ⁸⁾ -NR ⁸ - or (C ₁ -C ₁₈₎ - alkylcarbonyloxy - (C ₁ -C ₆₎ - Yes alkoxycarbonyl;

R ⁴ , R ⁵ , R ⁶ and R ⁷ , independently of one another, are H, fluorine, OH, (C ₁ -C ₈ ) -alkyl, (C ₃ -C).
₁₂₎ - cycloalkyl, (C ₃ -C ₁₂₎ - cycloalkyl -
(C ₁ -C ₈ ) -Alkyl, or R ⁸ OR ⁹ , R ⁸ SR ⁹ , R
_{^{8 CO 2 R 9, R 8}} OC (O) R 9, R 8 - (C 5 -C 14) - aryl ^{-R 9, R 8 N (R} 2) R 9, R 8 R 8 NR 9, R 8 N (R ² )
C (O) OR ⁹ , R ⁸ S (O) _n N (R ² ) R ⁹ , R ⁸ OC (O) N
(R ² ) R ⁹ , R ⁸ C (O) N (R ² ) R ⁹ , R ⁸ N (R ² ) C (O) N
(R ² ) R ⁹ , R ⁸ N (R ² ) S (O) _n N (R ² ) R ⁹ , R ⁸ S (O) _n
R ⁹ , R ⁸ SC (O) N (R ² ) R ⁹ , R ⁸ C (O) R ⁹ , R ⁸ N (R
² ) C (O) R ⁹ or R ⁸ N (R ² ) S (O) _n R ⁹ ; R
⁸ is H, (C ₁ -C ₈ ) -alkyl, (C ₃ -C ₁₂ ) -cycloalkyl, (C ₃ -C ₁₂ ) -cycloalkyl- (C ₁ -C ₈ ).
- alkyl, (C ₅ -C ₁₄₎ aryl or (C ₅ -C ₁₄₎ -
Aryl- (C ₁ -C ₈ ) -alkyl [wherein the alkyl group can be substituted by one or more than one fluorine]; R ⁹ is a single direct bond or (C ₁
-C ₈₎ - be a alkanediyl; R ¹⁰ is, C (O) R ^11,
4-8-containing 1, 2, 3 or 4 heteroatoms from the group of C (S) R ¹¹ , S (O) _n R ¹¹ , P (O) R ¹¹ _n or N, O and S Membered saturated or unsaturated heterocycles, for example:
Is tetrazolyl, imidazolyl, pyrazolyl, oxazolyl or thiadiazolyl; R ¹¹ is OH, (C _1-
C ₈₎ - alkoxy, (C ₅ -C ₁₄₎ - aryl - (C ₁ -
C ₈₎ - alkoxy, (C ₅ -C ₁₄₎ - aryloxy, (C
₁ -C ₈₎ - alkylcarbonyloxy - (C ₁ -C ₄₎ - alkoxy, (C ₅ -C ₁₄₎ - aryl - (C ₁ -C ₈₎ - alkylcarbonyloxy - (C ₁ -C ₆₎ - Alkoxy, NH
₂ , mono- or di (C ₁ -C ₈ -alkyl) amino, (C ₅
-C ₁₄₎ - aryl - (C ₁ -C ₈₎ - alkylamino, (C
₁ -C ₈₎ - dialkylaminocarbonyloxy methyloxy,
(C ₅ -C ₁₄₎ - aryl - (C ₁ -C ₈₎ - dialkylaminocarbonyl methyloxy or (C ₅ -C ₁₄₎ - aryl amino or L- or D- amino acid;

R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are, independently of one another, H, optionally substituted by one or more fluorines (C ₁ -C ₁₀ ). - alkyl, (C ₃ -C ₁₂₎ - cycloalkyl, (C ₃ -C ₁₂₎ - cycloalkyl - (C ₁ -C ₈₎ - alkyl, (C ₅ -C ₁₄₎ - aryl, (C ₅ -C ₁₄₎ - aryl - (C ₁ -C ₈₎ - ^{_{alkyl, H 2 N, R 8 ONR}} 9, R 8 OR 9, R 8 OC (O) R 9,
^{R 8 R 8 NR 9, R} 8 - (C 5 -C 14) - aryl -R ^9, HO
- (C ₁ -C ₈₎ - alkyl ^{-N (R 2) R 9,} R 8 N (R 2) C
(O) R ⁹ , R ⁸ C (O) N (R ² ) R ⁹ , R ⁸ C (O) R ⁹ , R ² R ^{3
N-C (= NR 2)} -NR 2 -, R 2 R 3 N-C (= NR 2),
═O or ═S and two adjacent substituents from the groups R ^{12 to} R ¹⁵ are taken together to form —OCH ₂ O—, —OC.
H ₂ CH ₂ O- or -OC (CH ₃₎ can be ₂ O- in which; R ¹⁶ is, H, optionally substituted by a number of fluorine than one or one optionally (C ₁ -C ₁₀₎ - alkyl, (C ₃ -C ₁₂₎ - cycloalkyl, (C ₃ -C ₁₂₎ -
Cycloalkyl - (C ₁ -C ₈₎ - alkyl, (C ₅ -C ₁₄₎
- aryl, (C ₅ -C ₁₄₎ - aryl - (C ₁ -C ₈₎ - alkyl, (C ₂ -C ₂₀₎ - alkenyl or (C ₂ -C ₂₀₎ -
Is alkynyl; m is 1, 2, 3, 4, 5 or 6
And n is 1 or 2; p and q are, independently of each other, 0 or 1; provided that R ¹ -AB-
D-C (R ¹⁶⁾ or ^{R 1 -A-B-D-} C (R 16) = C is ^{R 1 -K-C (R 16} ) or ^{R 1 -K-CH = O (} R 16 = H)
[In this case, R ¹ is X-NH-C (= NH)-
^{_{(CH 2) p, X 1}} -NH- (CH 2) p or 4-imidazolyl -CH ₂ - (p can be an integer of 0 to 3)
And

X is hydrogen, (C₁-C₆) -Alkyl, (C₁
-C₆) -Alkylcarbonyl, (C₁-C₆) -Alkoxy
Carbonyl, (C₁-C₁₈) -Alkylcarbonyloxy
-(C₁-C₆) -Alkoxycarbonyl, (C₆-C₁₄) −
Arylcarbonyl, (C₆-C ₁₄) -Aryloxyca
Lubonyl, (C₆-C₁₄) -Aryl- (C₁-C₆) -Al
Coxycarbonyl, hydroxyl, (C₁-C₆) -Arco
Kish, (C₆-C₁₄) -Aryl- (C₁-C₆) -Alkoki
Si or amino (the aryl group in X is optionally 1
Be replaced by one or more than one substitution
A good pure carbocycle) and X¹Is (C_Four-C₁₄)
-Arylcarbonyl, (C_Four-C₁₄) -Aryloxy
Carbonyl, (C_Four-C₁₄) -Aryl- (C₁-C₆) -A
Lucoxycarbonyl, (C_Four-C₁₄) -Aryl- (C₁−
C₆) -Alkoxy or R'-NH-C (= N-R ")
(In the formula, R ′ and R ″ independently of each other have the meaning of X.
Have and X¹1 aryl group in the case
Or may be replaced by more than one replacement
Is a pure carbocycle) and K is (C₁-C₆) -A
Lecan diyl, (C_Three-C₇) -Cycloalkanediyl, fu
Phenylene, phenylene- (C₁-C₆) -Alkanediyl,
(C₁-C₆) -Alkanediylphenylene, phenylene-
(C_Two-C₆) -Alkenediyl or 1 or 2 nitrites
Containing elementary atoms and one or two (C₁-C₆) -A
Replaced by rutile or doubly-bound oxygen or sulfur
Optionally saturated 5- or 6-membered saturated or unsaturated
A divalent group of the ring].

The alkyl groups found in the substituents are straight-chain or branched and one or more than one saturated or unsaturated. The same applies in a corresponding manner to radicals derived therefrom, eg alkoxy. Cycloalkyl is monocyclic, bicyclic or tricyclic. Monocyclic cycloalkyl groups are especially cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Cyclopeptyl and cyclooctyl. However, these cycloalkyl groups are, for example, (C ₁ -C ₄ ).
-Optionally substituted by alkyl. Examples of substituted cycloalkyl groups that may be mentioned are 4-methylcyclohexyl and 2,3-dimethylcyclopentyl.

Bicyclic and tricyclic cycloalkyl groups are
Unsubstituted or in any suitable position, one or more oxo groups and / or 1
Or two or more identical or different (C ₁ -C ₄ ) -alkyl groups, for example methyl or isopropyl groups, preferably methyl groups. The free bond of a bicyclic or tricyclic group can be located at any position in the molecule. As a result, these groups can be attached by bridgehead atoms or atoms in the bridge. The free bond can also be located at any stereochemical position, for example an exo position or an endo position.

Examples of original compounds of the bicyclic ring system are norbornane (= bicyclo [2.2.1] heptane), bicyclo [2.2.2] octane and bicyclo [3.2.1] octane. Is. An example of a system substituted with an octane group is camphor (= 1,7,7-trimethyl-2-oxobicyclo [2.2.1] heptane). An example of the original compound of the tricyclic system is Twistane (= tricyclo [4.4.0.
0 ^3.8 ] decane), adamantane (= tricyclo [3.
3.1.1 ^3.7 ] decane), noradamantane (= tricyclo [3.3.1.0 ^3.7 ] nonane), tricyclo [2.2.
1.0 ^2.6] heptane, tricyclo [5.3.2.0 ^4.9] dodecane, tricyclo [5.4.0.0 ^2.9] undecane or tricyclo [5.5.1.0 ^3.11] it is tridecane.

Examples of aryl are phenyl, naphthyl, biphenylyl, anthryl or fluorenyl,
1-naphthyl, 2-naphthyl and especially phenyl are preferred. Aryl groups, especially phenyl groups, are (C ₁ -C ₈ ) -alkyl, especially (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₈ ) -alkoxy, especially (C ₁ -C ₄ ) -alkoxy, Halogen such as fluorine, chlorine and bromine, nitro, amino, trifluoromethyl, hydroxyl, methylenedioxy, ethylenedioxy, —OC (CH ₃ ) ₂ O—, cyano, hydroxycarbonyl, aminocarbonyl, (C ₁ -C ₄ ) -alkoxycarbonyl, phenyl, phenoxy, benzyloxy,
(R ¹⁷ O) ₂ P (O), (R ¹⁷ O) ₂ P (O) -O- (in the formula, R ¹⁷
Is H, (C ₁ -C ₁₈ ) -alkyl, (C ₆ -C ₁₄ ) -aryl or (C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₈ ) -alkyl) or from the group of tetrazolyls May be substituted by one or more than one, preferably 1, 2 or 3 identical or different groups.

In mono-substituted phenyl groups, the substituents are 2-position, 3-position or 4-position, preferably 3 position.
-Position Can be located in many 4-positions. If the phenyl is substituted twice, the substituents can be in the 1,2-position, the 1,3-position or the 1,4-position with respect to each other. Preferably, in a twice substituted phenyl group, the substituents are arranged in the 3 and 4-positions based on the binding site. Aryl groups also include mono- or polycyclic aromatic ring systems in which 1 to 5 carbon atoms may be replaced by 1 to 5 heteroatoms, such as 2-pyridyl, 3-pyridyl, 4 -Pyridyl, pyrrolyl, furyl,
Thienyl, imidazolyl, pyrazolyl, oxazolyl,
Isoxazolyl, thiazolyl, isothiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, isoindolyl, indazolyl, phthalazinyl,
It can also be a quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, β-carbolinyl or benzo-fused, cyclopenta-fused, cyclohexa-fused or cyclohepta-fused derivative of these groups. These heterocycles may be substituted with the same substituents as the carbocyclic aryl system described above.

In this system of aryl groups, preferred groups have 1 to 3 heteroatoms from the group N, O and S and are (C ₁ -C ₆ ) -alkyl, (C ₁ -C _6). ) -Alkoxy, fluorine, Cl, NO ₂ , NH ₂ , trifluoromethyl,
OH, (C ₁ -C ₄ ) -alkoxycarbonyl, phenyl,
A monocyclic or bicyclic aromatic ring system optionally substituted with 1 to 3 substituents from the group of phenoxy, benzyloxy or benzyl. Particularly preferred aryl groups in this connection are (C ₁ -C ₄ ) -alkyl, (C _1- ).
C ₄ ) -Alkoxy, phenyl, phenoxy, benzyl or 1-3 from the group of N, O and S optionally substituted by 1 to 2 substituents from the group of benzyloxy.
Mono- or bicyclic aromatics having 5 heteroatoms 5
It is a 10-membered ring system.

What has been said above is in a corresponding manner derived from alkyl, cycloalkyl and aryl 2
It applies to valent groups such as alkanediyl, alkenediyl, alkynediyl, cycloalkanediyl and arylene. Also preferred are compounds of formula I having a lipophilic group R ⁴ , R ⁵ , R ⁶ or R ⁷ such as benzyloxycarbonylamino, cyclohexylmethylcarbonylamino and the like.

In addition, R ¹ may optionally contain 1 to 4 heteroatoms from the group N, O and S and optionally R ¹² , R ¹³ , R ¹⁴ and R ¹⁵
A 4- to 14-membered monocyclic or polycyclic aromatic or non-aromatic ring system optionally substituted by one or more substituents from the group

[0025]

[Chemical 21]

[0026]

Embedded image Formula I, where Y'is NR ² , O or S
Are preferred.

L- or D-amino acids are natural or unnatural amino acids. α-amino acids are preferred. These amino acids that can be mentioned by way of example are (Houben
-Weyl, Methoden der organischen Chemie 〔Methods of
Organic Chemistry], Volume XV / 1 and 2, Georg Th
ieme Verlag, Stuttgart, 1974): Aad, Ab
u, γAbu, ABz, 2ABz, εAca, Ach,
Acp, Adpd, Ahb, Aib, βAib, Al
a, βAla, ΔAla, Alg, All, Ama, A
mt, Ape, Apm, Apr, Arg, Asn, As
p, Asu, Aze, Azi, Bai, Bph, Ca
n, Cit, Cys, (Cys) ₂ , Cyta, Daa
d, Dab, Dadd, Dap, Dapm, Dasu,
Djen, Dpa, Dtc, Fel, Gln, Glu,
Gly, Guv, hAla, hArg, hCys, hG
ln, hGlu, His, hlle, hLeu, hLy
s, hMet, hPhe, hPro, hSer, hTh
r, hTrp, hTyr, Hyl, Hyp, 3Hyp,
Ile, Ise, Iva, Kyn, Lant, Lcn,
Leu, Lsg, Lys, βLys, ΔLys, Me
t, Mim, Min, nArg, Nle, Nva, Ol
y, Orn, Pan, Pec, Pen, Phe, Ph
g, Pic, Pro, ΔPro, Pse, Pya, Py
r, Pza, Qin, Ros, Sar, Sec, Se
m, Ser, Thi, βThi, Thr, Thy, Th
x, Tia, Tle, Tly, Trp, Trta, Ty
r, Val, tert-butylglycine (Tbg), neopentylglycine (Npg), cyclohexylglycine (Chg), cyclohexylalanine (Cha), 2-
Thienylalanine (Thia), 2,2-diphenylaminoacetic acid, 2- (p-tolyl) -2-phenylaminoacetic acid and 2- (p-chlorophenyl) aminoacetic acid;

And further: pyrrolidine-2-carboxylic acid; piperidine-2-carboxylic acid; 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; decahydroisoquinoline-3-carboxylic acid; octahydroindole- 2-carboxylic acid; decahydroquinoline-2-carboxylic acid; octahydrocyclopenta [b] pyrrole-2-
Carboxylic acid; 2-azabicyclo [2.2.2] octane-
3-carboxylic acid; 2-azabicyclo [2.2.1] -heptane-3-carboxylic acid; 2-azabicyclo [3.1.0]
Hexane-3-carboxylic acid; 2-azaspiro [4.4]
Nonane-3-carboxylic acid; 2-azaspiro [4.5] decane-3-carboxylic acid; spiro (bicyclo [2.2.1])
Heptane) -2,3-pyrrolidine-5-carboxylic acid; spiro (bicyclo [2.2.2] octane) -2,3-pyrrolidine-5-carboxylic acid; 2-azatricyclo [4.3.
0.1 ^{6, 9]} decane-3-carboxylic acid; decahydro cycloheptanone [b] pyrrole-2-carboxylic acid; decahydro-cyclooctadiene [c] pyrrole-2-carboxylic acid; octahydrocyclopenta [b] pyrrole 2-carboxylic acid; octahydroisoindole-1-carboxylic acid; 2,3,3
a, 4,6a-Hexahydrocyclopenta [b] pyrrole-2-carboxylic acid; 2,3,3a, 4,5,7a-hexahydroindole-2-carboxylic acid; tetrahydrothiazole-4-carboxylic acid; isoxazolidine -3-carboxylic acid; pyrazolidine-3-carboxylic acid and hydroxypyrrolidine-2-carboxylic acid (these may be optionally substituted) (see formula below):

[0029]

Embedded image It is.

Heterocycles based on the groups mentioned above are, for example:
US-A-4,344,949; US-A 4,374,8.
47; US-A 4,350,704; EP-A 29,4.
88; EP-A 31,741; EP-A 46,953;
EP-A 49,605; EP-A 49,658; EP-
A 50,800; EP-A 51,020; EP-A 5
2,870; EP-A 79,022; EP-A 84,1
64; EP-A 89,637; EP-A 90,341;
EP-A 90,362; EP-A 105,102; EP
-A 109,020; EP-A 111,873; EP-
A 271,865 and EP-A 344,682. Furthermore, the amino acids are also esters or amides, such as methyl esters, ethyl esters, isopropyl esters, isobutyl esters, tert-butyl esters, benzyl esters, ethylamides, semicarbazides or ω-amino- (C ₂ -C ₈ ) -alkylamides. Can also be given as

The functional groups of amino acids can be protected. Suitable protecting groups such as urethane protecting groups, carboxyl protecting groups and side chain protecting groups are described in Hubbuch, Kontakte (Mer
ck) 1979, No. 3, pages 14-23 and Buellesbach, Kontakte.
(Merck) 1980, No. 1, pages 23-35. Protecting groups that may be mentioned in particular are Aloc, Pyoc, F
moc, Tcboc, Z, Boc, Ddz, Bpoc,
Adoc, Msc, Moc, Z (NO ₂ ), Z (Hal _n ),
Bobz, Iboc, Adpoc, Mboc, Acm,
Tertiary butyl, OBzl, ONbzl, OMbzl, Bz
l, Mob, Pic, Trt.

Physiologically acceptable salts of the compounds of formula I are especially the pharmaceutically usable or non-toxic salts.
These salts include, for example, alkali metal or alkaline earth metals such as Na, K, Mg and Ca and also physiologically acceptable organic amines such as triethylamine, ethanolamine or tris- (2-hydroxyethyl). ) -Amine is used to form compounds of formula I containing an acidic group such as a carboxyl.
Compounds of formula I containing a basic group such as an amino group, an amidino group or a guanidino group can be treated with an inorganic acid such as hydrochloric acid,
Sulfuric acid or phosphoric acid and also organic carboxylic acids or sulphonic acids such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulphonic acid or p-
Forms a salt with toluenesulfonic acid.

The novel compounds of formula I can contain optically active carbon atoms and these can, independently of one another, have the R or S configuration. as a result,
These compounds can be present in the form of pure enantiomers or pure diastereomers or in the form of enantiomeric mixtures or diastereomeric mixtures. Both the pure enantiomers and enantiomeric mixtures and also diastereomers and diastereomeric mixtures are part of the subject matter of the invention. The novel compounds of formula I can contain transferable hydrogen atoms and, as a result, can exist in different tautomeric forms. These tautomers are also part of the subject matter of the invention.

A, D or F are, independently of each other, -CR
^{2 = CR 3 -, - NR} 2 -N = CR 2 -, - N = CR 2 - or -R ² C = a N- and (or) B is -CR ²
= CR ³ − and / or W is R ¹ −A−B−D
-C (R ¹⁶ ) = C or

Embedded image Where, the novel compounds of formula I can exist as E / Z isomer mixtures. The present invention relates to pure E or Z isomers and E / Z isomer mixtures. E /
Diastereomers, including Z isomers, can be separated into individual isomers by chromatography. Racemates can be separated into two enantiomers by chromatography on a chiral phase or by racemic resolution.

W is R ^1- A-B-D-C (R ¹⁶ ), R ^1-
A-B-D-C (R ¹⁶ ) = C,

Embedded image [Wherein the ring system

Embedded image Contains 1 or 2 heteroatoms from the group N and O, may be 1 saturated or unsaturated and is substituted by 1 or 2 substituents from R ^16. May be present]; Y is C = O, C = S or -CH
₂ -; Z is, -N (R ^0), O or -CH ₂ -; A is a single direct bond, (C ₁ -C ₆₎ - alkanediyl, -NR ² -N ^{= CR 2 -, - NR 2} -C (O) -N
^{R 2 -, - NR 2 -C} (O) O -, - NR 2 -C (O) S-,
^{-NR 2 -C (S) -NR 2} -, - NR 2 -C (S) -O-,
^{-NR 2 -C (S) -S -} , - NR 2 -S (O) n -NR 2 -,
_{^{-NR 2 -S (O) n -O}} -, - NR 2 -S (O) n -, (C 3 -
C ₈₎ - cycloalkyl alkanediyl, -C≡C -, - NR ² -
C (O) -, - C (O) -NR 2 -, - (C 5 -C 12) - arylene ^{-C (O) -NR 2 -,} - O-, S (O) n -, - (C ₅ −
C ₁₂₎ - arylene -, - CO -, - ( C 5 -C 12) - arylene ^{-CO -, - NR 2 -,} - SO 2 -NR 2, -C
(O) O -, - O -C (O) -, - N = CR 2 -, - R 2 C =
^{N -, - CR 2 = CR} 3 -, - (C 5 -C 12) - arylene -S (O) _n - [these groups, and in each case may be substituted by NR ² ( Or) optionally substituted by one or two (C ₁ -C ₈ ) -alkanediyl]; B is a single direct bond, (C ₁ -C ₆ ) -alkanediyl, (C ₅ -C ₈ ) -Arylene, (C ₃ -C ₈ ) -Cycloalkanediyl, -C≡C
^{-, - NR 2 -, -} C (O) -, - NR 2 -C (O) -, - C
^{(O) -NR 2 -, -} NR 2 -C (O) -NR 2 -, - S (O)
_{-, - S (O) 2} -, - S (O) -NR 2 -, - S (O) 2 -N
^{R 2 -, - NR 2 -S} (O) -, - NR 2 -S (O) 2 -, - O
^{-, - CR 2 = CR 3} - [these groups, in each case, one or two (C ₁ -C ₆₎ - alkanediyl which may be substituted by] be; D is, single direct bond, (C ₁ -C ₈₎ - alkanediyl, (C ₅ -C ₈₎
- ^{arylene, -O -, - NR 2 -} , - CO-NR 2 -,
^{-NR 2 -CO -, - NR 2} -C (O) -NR 2 -, - NR 2
^{-C (S) -NR 2 -,} - OC (O) -, - C (O) O -, -
CO-, -CS-, -S (O)-, -S (O) _2- , -S
^{_{(O) 2 -NR 2 -,}} - NR 2 -S (O) -, - NR 2 -S (O)
_{2 -, - S -, -} CR 2 = CR 3 -, - C≡C -, - NR 2
^{-N = CR 2 -, - N} = CR 2 - or -R ² C = N-
[These radicals are in each case one or two (C ₁ -C ₆ ) -alkanediyl, —CR ² ═CR ³ —
Or (C ₅ -C ₆ ) -arylene may be substituted]; E is a single direct bond, (C ₁ -C ₄ )-
Alkanediyl, (C ₂ -C ₄₎ - alkenediyl, (C ₂ -
C ₄₎ - alkynediyl, phenylene, phenylene - (C ₁
-C ₂₎ - alkanediyl or (C ₁ -C ₂₎ - be a alkanediyl phenylene; F is are as defined as D; G is,

[0036]

Embedded image L is C (R ¹⁶ ), or N; R ⁰ is H,
(C ₁ -C ₈ ) -alkyl, (C ₃ -C ₈ ) -cycloalkyl,
(C ₃ -C ₈₎ - cycloalkyl - (C ₁ -C ₆₎ - alkyl,
(C ₅ -C ₁₂₎ - aryl, (C ₅ -C ₁₂₎ - aryl - (C ₁
-C ₆₎ - alkyl, (C ₁ -C ₈₎ - alkyl -C (O),
(C ₃ -C ₈₎ - cycloalkyl _{-C (O), (C 3} -C 8) - cycloalkyl - (C ₁ -C ₄₎ - alkyl _{-C (O), (C 5} -
C ₁₂ ) -Aryl-C (O) or (C ₅ -C ₁₂ ) -aryl- (C ₁ -C ₄ ) -alkyl-C (O) [wherein the alkyl group is one or more than one fluorine be optionally substituted]; R ^{1 is, R 2 -C (= NR 2} ) NR 3 -, R 2 R 3
^{N-C (= NR 2)} -, R 2 R 3 N-C - (= NR 2) -NR 2
Or optionally 1-4 from a group of N, O and S
4 heteroatoms and optionally 1 or more than one R ¹² , R ¹³ , R ¹⁴ and R
4 to 1 optionally substituted with substituents from the group of ¹⁵
A 0-membered mono- or polycyclic aromatic or non-aromatic ring system;

R ² and R ³ , independently of one another, are (C ₁ -C ₈ ) -alkyl, (C ₃ optionally substituted by H, optionally one or more than one fluorine). -C ₈₎ -
Cycloalkyl, (C ₃ -C ₈₎ - cycloalkyl - (C ₁ -
C ₆₎ - alkyl, (C ₅ -C ₁₂₎ - aryl, (C ₅ -C ₁₂₎
- aryl - (C ₁ -C ₆₎ - alkyl, H ₂ N, R ⁸ ONR
^{9, R 8 OR 9, R} 8 OC (O) R 9, R 8 - (C 5 -C 12) - aryl ^{-R 9, R 8 R 8 NR} 9, HO- (C 1 -C 8) - alkyl ^{-NR 8 R 9, R 8 R} 8 NC (O) R 9, R 8 C (O) NR
⁸ R ⁹ , R ⁸ C (O) R ⁹ , R ⁸ R ⁸ NC (= NR ⁸ )-, R ⁸ R
^{8 N-C (= NR 8} ) -NR 8 - or (C ₁ -C ₁₀₎ - alkylcarbonyloxy - (C ₁ -C ₄₎ - alkoxycarbonyl ^{carbonyloxy; R 4, R 5, R} 6 and R ⁷ Independently of each other, H, fluorine, OH, (C ₁ -C ₈ ) -alkyl, (C ₅ -C
₁₂₎ - cycloalkyl, (C ₅ -C ₁₂₎ - cycloalkyl -
(C ₁ -C ₈ ) -Alkyl or R ⁸ OR ⁹ , R ⁸ SR ⁹ , R ^{8
_{CO 2 R 9, R 8 OC}} (O) R 9, R 8 - (C 5 -C 12) - aryl ^{-R 9, R 8 N (R} 2) R 9, R 8 R 8 NR 9, R 8 N (R ² ) C
(O) OR ⁹ , R ⁸ S (O) _n N (R ² ) R ⁹ , R ⁸ OC (O) N
(R ² ) R ⁹ , R ⁸ C (O) N (R ² ) R ⁹ , R ⁸ N (R ² ) C (O) N
(R ² ) R ⁹ , R ⁸ N (R ² ) S (O) _n N (R ² ) R ⁹ , R ⁸ S (O) _n
R ⁹ , R ⁸ SC (O) N (R ² ) R ⁹ , R ⁸ C (O) R ⁹ , R ⁸ N (R
² ) C (O) R ⁹ , R ⁸ N (R ² ) S (O) _n R ⁹ ; R ⁸ is
_{H, (C 1 -C 6)} - alkyl, (C ₅ -C ₁₂₎ - cycloalkyl, (C ₅ -C ₁₂₎ - cycloalkyl - (C ₁ -C ₆₎ - alkyl, (C ₅ -C ₁₂ ) Aryl or (C ₅ -C ₁₂ ) -aryl- (C ₁ -C ₆ ) -alkyl [wherein the alkyl group may be substituted by one or more than one fluorine];

R ⁹ is a single direct bond or (C _1-
C ₆₎ - be a alkanediyl; R ^{10 is, C (O) R 11,} C
(S) R ¹¹ , S (O) _n R ¹¹ , P (O) R ¹¹ _n or 4-8-members containing 1, 2, 3 or 4 heteroatoms from the group N, O and S. A saturated or unsaturated heterocycle of R;
¹¹ is OH, (C ₁ -C ₆ ) -alkoxy, (C ₅ -C ₁₂ )-
Aryl - (C ₁ -C ₆₎ - alkoxy, (C ₅ -C ₁₂₎ - aryloxy, (C ₁ -C ₆₎ - alkylcarbonyloxy - (C ₁ -C ₄₎ - alkoxy, (C ₅ -C ₁₂ ) -Aryl-
(C ₁ -C ₆ ) -Alkylcarbonyloxy- (C ₁ -C ₆ )-
Alkoxy, NH _2, mono- - or di (C ₁ -C ₆ - alkyl) amino, (C ₅ -C ₁₂₎ - aryl - (C ₁ -C ₆₎ - alkylamino or (C ₁ -C ₆₎ - dialkyl Aminocarbonylmethyloxy; R ¹² , R ¹³ , R ¹⁴ and R
¹⁵ may, independently of one another, be substituted by H, optionally one or more than one fluorine (C _1-
C ₈₎ - alkyl, (C ₃ -C ₈₎ - cycloalkyl, (C ₃ -
C ₈₎ - cycloalkyl - (C ₁ -C ₆₎ - alkyl, (C ₅ -
C ₁₂₎ - aryl, (C ₅ -C ₁₂₎ - aryl - (C ₁ -C ₆₎
- ^{_{alkyl, H 2 N, R 8 ONR}} 9, R 8 OR 9, R 8 OC
^{(O) R 9, R 8} - (C 5 -C 12) - aryl -R ^9, R ⁸ R ⁸ N
_{^{R 9, HO- (C 1 -C}} 8) - alkyl ^{-N (R 2) R 9,} R 8 N
(R ² ) C (O) R ⁹ , R ⁸ C (O) N (R ² ) R ⁹ , R ⁸ C (O)
^{R 9, R 2 R 3 N} -C (= NR 2) -, R 2 R 3 N-C (= N
R ³⁾ -NR ² -, a = O or = S and the radicals R ¹² ~
Two adjacent substitutions from R ¹⁵ are also taken together to form -O.
_{CH 2 O -, - OCH 2} CH 2 O- or -OC (CH _{3) 2}
May be O--; R ¹⁶ may be substituted by H, optionally one or more than one fluorine
(C ₁ -C ₈ ) -alkyl, (C ₃ -C ₈ ) -cycloalkyl,
(C ₃ -C ₈₎ - cycloalkyl - (C ₁ -C ₆₎ - alkyl,
(C ₅ -C ₁₂₎ - aryl, (C ₅ -C ₁₂₎ - aryl - (C ₁
-C ₆₎ - alkyl, (C ₂ -C ₈₎ - alkenyl, or (C ₂
-C ₈₎ - alkynyl; m is located at 3, 4 or 5; n is 1 or 2; and p and q, compounds of formula I in which independently of one another 0 or 1 and their Physiologically acceptable salts are preferred. W is R ¹ -AB
^{-D-C (R 16),} R 1 -A-B-D-C (R 16) = C or

[0039]

Embedded image In it; Y is, C = O, C = S or -CH ₂ -, preferably it is a C = O or C = S; Z is, N (R ⁰⁾ or -CH ₂ -, preferably N (R ⁰ ); A is a single direct bond, (C ₁ -C ₆ ) -alkanediyl, —NR ² —
^{N = CR 2 -, - NR} 2 -C (O) -NR 2 -, - NR 2 -C
(O) O -, - NR 2 -C (O) S -, - NR 2 -S (O) n -
^{NR 2 -, - NR 2 -S} (O) n -, (C 3 -C 6) - ^{cycloalkanediyl, -C≡C -, - NR 2 -C} (O) -, - C
^{(O) -NR 2 -, (} C 5 -C 10) - arylene -C (O) -N
^{R 2 -, - O -,} (C 5 -C 10) - arylene -, - CO
_{-, - (C 5 -C 10} ) - arylene -CO -, - NR ² -,
-C (O) O -, - N = CR 2 -, - R 2 C = N- or -
CR ² = CR ³ [These radicals are in each case optionally substituted by NR ² and / or by one or two (C ₁ -C ₆ ) -alkanediyl B] is a single direct bond, (C ₁ -C ₆ ) -alkanediyl, (C ₅ -C ₆ ) -arylene, (C ₅ -C ₆ ) -cycloalkanediyl,- C≡C
^{-, - NR 2 -C (O} ) -, - C (O) -NR 2 -, - NR 2
—S (O) ₂ —, —O— or —CR ² ═CR ³ — [these radicals are in each case one or two
(C ₁ -C ₆ ) -Alkanediyl may be substituted].

D is a single direct bond, (C ₁ -C ₆ ) -alkanediyl, (C ₅ -C ₆ ) -arylene, -O-, -N
^{R 2 -, - NR 2 -CO} -, - NR 2 -C (O) -NR 2 -,
^{-NR 2 -C (S) -NR 2} -, - OC (O) -, - C (O)
_{-, - S (O) 2} -NR 2 -, - NR 2 -S (O) -, - NR 2
_{-S (O) 2 -, -} N = CR 2 - or -R ² C = N-[these groups, in each case, one or two (C ₁ -C ₆₎ - by alkanediyl May be substituted]; E is a single direct bond, (C ₁ -C ₄ )-
Alkanediyl or (C ₂ -C ₄₎ - be alkenediyl; F is a single direct bond, (C ₁ -C ₆₎ - alkanediyl, -O -, - CO-NR 2 -, - NR 2 -CO-,-
^{NR 2 -C (O) -NR 2} -, - OC (O) -, - C (O) O
-, - CO -, - S (O) 2 -, - S (O) 2 -NR 2 -, -
_{^{NR 2 -S (O) 2 -}} , - CR 2 = CR 3 -, - C≡C -, -
N = CR ² - or -R ² C = N-[these groups, one or two in each case (C ₁ -C ₆₎ - alkanediyl which may be substituted by] be;

G is

Embedded image L is C (R ¹⁶ ), or N; R ⁰ is H,
(C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl,
(C ₃ -C ₆₎ - cycloalkyl - (C ₁ -C ₄₎ - alkyl,
(C ₅ -C ₁₀₎ - aryl, (C ₅ -C ₁₀₎ - aryl - (C ₁
-C ₄₎ - alkyl, (C ₁ -C ₆₎ - alkyl -C (O) -,
(C ₅ -C ₆ ) -Cycloalkylmethyl-C (O)-, phenyl-C (O) or benzyl-C (O) [wherein the alkyl group is 1 to
Optionally substituted by 6 fluorines]; R
^{1, R 2 -C (= NR 2} ) NR 2 -, R 2 R 3 N-C (= N
R ² )-

[0042]

Embedded image

[0043]

Embedded image Wherein Y ′ is NR ² , O or S; R ²
And R ³ independently of one another are H, optionally 1
Or more than one, preferably 1 to 6, (C ₁ -C ₆ ) -alkyl optionally substituted with fluorine, (C ₃
-C ₆₎ - cycloalkyl, (C ₃ -C ₆₎ - cycloalkyl - (C ₁ -C ₄₎ - alkyl, (C ₅ -C ₁₀₎ - aryl, (C
₅ -C ₁₀₎ - aryl - (C ₁ -C ₄₎ - alkyl, H ₂ N,
^{R 8 OR 9, R 8 -} (C 5 -C 10) - aryl -R ^9, R ⁸ NH
^{R 9, R 8 R 8 NR} 9, R 8 NHC (O) R 9, R 8 C (O) -,
_{H 2 N-C (= NH} ) or _{H 2 N-C (= NH} ) -NH- and ^{have; R 4, R 5, R} 6 and R ^7, independently of one another,
H, _{fluorine, OH, (C 1 -C 6} ) - alkyl, (C ₆ -C ₁₂₎
- cycloalkyl, (C ₆ -C ₁₂₎ - cycloalkyl - (C
₁ -C ₆₎ - alkyl or ^{R 8 OR 9, R 8 CO} 2 R 9, R 8
^{OC (O) R 9, R} 8 - (C 5 -C 10) - aryl -R ^9, R ⁸
NHR ⁹ , R ⁸ R ⁸ NR ⁹ , R ⁸ NHC (O) OR ⁹ , R ⁸ S
(O) _n NHR ⁹ , R ⁸ OC (O) NHR ⁹ , R ⁸ C (O) NH
R ⁹ , R ⁸ C (O) R ⁹ , R ⁸ NHC (O) NHR ⁹ , R ⁸ NHS
(O) _n NHR ⁹ , R ⁸ NHC (O) R ⁹ , R ⁸ NHS (O) _n R ⁹
Is;

R ⁸ is H, (C ₁ -C ₆ ) -alkyl, (C ₆
-C ₁₂₎ - cycloalkyl, (C ₆ -C ₁₂₎ - cycloalkyl - (C ₁ -C ₄₎ - alkyl, (C ₅ -C ₁₀₎ - aryl or (C ₅ -C ₁₀₎ - aryl - ( C ₁ -C ₄ ) -alkyl [wherein the alkyl group may be substituted by 1 to 6 fluorine atoms]; R ⁹ is a single direct bond or
(C ₁ -C ₆ ) -alkanediyl; R ¹⁰ is C (O) R
¹¹ , S (O) _n R ¹¹ or P (O) R ¹¹ _n ; R ¹¹ is O
H, (C ₁ -C ₆₎ - alkoxy, (C ₅ -C ₁₀₎ - aryl - (C ₁ -C ₆₎ - alkoxy, (C ₅ -C ₁₀₎ - aryloxy, (C ₁ -C ₆₎ - alkylcarbonyloxy - (C ₁ -
C ₄₎ - alkoxy, (C ₅ -C ₁₀₎ - aryl - (C ₁ -
C ₄₎ - alkylcarbonyloxy - (C ₁ -C ₄₎ - alkoxy, NH ₂ or mono- - or di (C ₁ -C ₆₎ - alkylamino; R ^12, R ¹³ and R ^14, H, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, (C ₃ -C ₆ ) -cycloalkyl optionally substituted by one or more than one fluorine - (C ₁ -C ₄₎
- alkyl, (C ₅ -C ₁₀₎ - aryl, (C ₅ -C ₁₀₎ - aryl - (C ₁ -C ₄₎ - ^{_{alkyl, H 2 N, R 8 OR}} 9, R 8
^{OC (O) R 9, R} 8 - (C 5 -C 10) - aryl -R ^9, R ⁸
R ⁸ NR ⁹ , R ⁸ NHC (O) R ⁹ , R ⁸ C (O) NHR ⁹ , H ₂
N-C (= NH) - , H 2 N-C (= NH) -NH- or = is O and two adjacent substituents from the group R ¹² to R ¹⁴ may also, taken together, -OCH ₂ O- or -OC
R ₂ may be H ₂ CH ₂ O—; R ¹⁶ is H, (C ₁ -C ₆ ) -alkyl optionally substituted by 1 to 6 fluorine, (C ₃ -C ₆ ) -cyclo alkyl, (C ₃ -C ₆₎ - cycloalkyl - (C ₁ -C ₄₎ - alkyl, phenyl, phenyl - (C ₁ -C ₄₎ - alkyl or (C ₂ -C ₆₎ - alkenyl; m Is 3, 4 or 5; n is 1 or 2; and p and q, independently of each other, are 0 or 1 and the physiologically acceptable salts thereof. preferable.

W is R ¹ -A-B-D-C (R ¹⁶ ) or R ¹ -A-B-D-CH = C; Y is C = O or C = S; Z Is N (R ⁰ ); A is a single direct bond, (C ₁ -C ₄ ) -alkanediyl, —NR ² —N
^{= CR 2 -, - NR 2} -C (O) -NR 2 -, - NR 2 -C
(O) O -, - NR 2 -S (O) n -, - NR 2 -S (O) n -N
^{R 2 -, - NR 2 -CO} -, - NR 2 - or -N = CR ²
[These groups may in each case be substituted by NH and / or by one or two (C ₁ -C ₄ ) -alkanediyl]; B is a single direct bond, (C ₁ -C ₄ )-
Alkanediyl, phenylene, pyridine, divalent group of thiophene or furan, cyclohexanediyl, -C≡
^{C -, - CR 2 = CR} 3 -, - C (O) -NR 2 - or -
NR ² -C (O)-[these groups may in each case be substituted by ₁ or 2 (C ₁ -C ₄ ) -alkanediyl]; A direct bond of (C ₁ -C ₄ ) -alkanediyl, phenylene, —O
^{-, - NR 2 -, -} NR 2 -C (O) -, - NR 2 -C (O)
^{-NR 2 -, - R 2 N} -S (O) 2 -NR 2 -, - NR 2 -S
_{(O) 2 -, - NR} 2 -S (O) -, - N = CR 2 - or -
R ² C = N- [these groups are in each case optionally substituted by ₁ or 2 (C ₁ -C ₄ ) -alkanediyl]; E is a single A direct bond or (C ₁ -C ₄ ) -alkanediyl; F is
Single direct bond, (C ₁ -C ₆ ) -alkanediyl, —O
^{-, - CO-NR 2 -} , - NR 2 -CO -, - NR 2 -C
^{(O) -NR 2 -, -} S (O) 2 -NR 2, -NR 2 -S (O) 2
^{-, - CR 2 = CR 3} -, - C≡C -, - N = CR 2 - or -R ² C = N-[these groups, one or two in each case (C ₁ - C ₄ ) -Alkanediyl may be substituted].

G is

Embedded image R ⁰ is H, (C ₁ -C ₆ ) -alkyl, trifluoromethyl, pentafluoroethyl, (C ₅ -C ₆ ) -cycloalkyl, (C ₅ -C ₆ ) -cycloalkyl- ( C ₁ -C ₂₎
-Alkyl, optionally substituted phenyl or benzyl optionally substituted on a phenyl group; R ¹ is R ² R ³ NC (= NR ² ),

[0047]

Embedded image

[0048]

Embedded image Where Y'is NH, O or S; R ²
And R ³ , independently of one another, are H, (C ₁ -C ₆ ) -alkyl, trifluoromethyl, pentafluoroethyl,
(C ₅ -C ₆₎ - cycloalkyl, (C ₅ -C ₆₎ - cycloalkyl - (C ₁ -C ₂₎ - alkyl, phenyl, benzyl, H
_{^{2 N, R 8 OR 9,}} R 8 - (C 5 -C 10) - aryl -R ^9, R
⁸ NHR ⁹ , R ⁸ R ⁸ NR ⁹ , R ⁸ NHC (O) R ⁹ , H ₂ N-C
(= NH) or _{H 2 C-C (= NH} ) -NH- and have;
R ⁴ , R ⁵ , R ⁶ and R ⁷ , independently of one another, are H, fluorine, OH, (C ₁ -C ₆ ) -alkyl, (C ₁₀ -C ₁₂ ) -cycloalkyl, (C _10- ). C ₁₂₎ - cycloalkyl - (C ₁ -C
₆₎ - alkyl or ^{R 8 OR 9, R 8 -} (C 5 -C 10) - aryl ^{-R 9, R 8 R 8 NR} 9, R 8 NHC (O) OR 9, R 8 S
(O) _n NHR ⁹ , R ⁸ OC (O) NHR ⁹ or R ⁸ C (O) N
HR ⁹ ; R ⁸ is H, (C ₁ -C ₆ ) -alkyl, (C
₁₀ -C ₁₂₎ - cycloalkyl, (C ₁₀ -C ₁₂₎ - cycloalkyl - (C ₁ -C ₂₎ - alkyl, (C ₅ -C ₁₀₎ - aryl or (C ₅ -C ₁₀₎ - aryl - (C ₁ -C ₂ ) -alkyl; R ⁹ is a single direct bond or (C ₁ -C ₆ ).
- be a alkanediyl; R ¹⁰ is located at C (O) R ^11;
R ¹¹ is OH, (C ₁ -C ₆ ) -alkoxy, phenoxy,
Benzyloxy, (C ₁ -C ₄ ) -alkylcarbonyloxy- (C ₁ -C ₄ ) -alkoxy, NH ₂ , mono- or di
(C ₁ -C ₆ -alkyl) amino; R ¹⁶ is H, (C ₁
-C ₄₎ - alkyl, trifluoromethyl, pentafluoroethyl, (C ₅ -C ₆₎ - cycloalkyl, (C ₅ -C ₆₎ -
Cycloalkyl- (C ₁ -C ₂ ) -alkyl, phenyl or benzyl; n is 1 or 2; and p
Very particular preference is given to compounds of the formula I and their physiologically tolerable salts, where and q are, independently of one another, 0 or 1.

Abbreviations used. Boc: t-butoxycarbonyl DCCI: dicyclohexylcarbodiimide DMF: dimethylformamide HOOBt: 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine THF: tetrahydrofuran HOBt: 1-hydroxybenzotriazole TOTU: O- [cyano (ethoxycarbonyl) methyleneamino] -1,1,3,3-tetramethyluronium DIPEA: diisopropylethylamine RT: room temperature Z: benzyloxycarbonyl

In general, the compounds of formula I can be prepared, for example, by coupling, during the conversion synthesis, two or more fragments which can be derived synthetically from formula I in reverse synthesis. In general, when preparing compounds of Formula I, functional groups that desirably undergo reactions or side-reactions in certain synthetic steps during the synthesis are temporarily protected during the synthesis by protecting group means known to those skilled in the art and adapted to the synthetic problem. Need to be blocked. The method of fragment attachment is not limited to the following examples, but is generally of formula I
Can be used to synthesize compounds of

For example, a type in which F is C (O) NR ^2.

Embedded image The compound of formula I

Embedded image (Wherein M is hydroxycarbonyl, (C ₁ -C ₆ ) -alkoxycarbonyl, an activated carboxylic acid derivative such as an acid chloride, an active ester or a mixed anhydride)
It can be produced by condensing the compound of 1) with HNR ² -G. To condense the two fragments to form an amide bond, coupling methods of peptide chemistry known per se are advantageously used (eg Houben-Weyl, M.
ethoden der Organischen Chemie 〔Methods of Organic
Chemistry), Volume 15/1 and 15/2, Georg Thieme Ve
rlag, Stuttgart, 1974). For this purpose, it is generally necessary for the non-reacting amino groups present to be protected by reversible protecting groups during the condensation. The same applies to carboxyl groups which do not participate in the reaction, this protecting group being preferably used as (C ₁ -C ₆ ) -alkyl, benzyl or tert-butyl ester. If the amino groups generated are present as nitro or cyano groups and are only formed by hydrogenation after coupling, amino group protection is no longer necessary. After coupling, the protecting groups present are removed in a suitable manner.
For example, NO ₂ groups (guanidino protected), benzyloxycarbonyl groups and benzyl esters can be removed by hydrogenation. Tertiary butyl type protecting groups are removed under acidic conditions, while 9-fluorenylmethyloxycarbonyl groups are removed using secondary amines.

[0052]

Embedded image A compound of formula I in which is a dioxo- or thiooxo-oxo-substituted imidazolidine ring (W is R ¹ -A-B-D-C (R ¹⁶ )) is, for example, an α-amino acid or an N-substituted Α-amino acid or preferably an ester thereof, such as methyl ester, ethyl ester, tert-butyl ester or benzyl ester, for example formula III

Embedded image Can be obtained, for example, by reacting with an isocyanate or isothiocyanate of the formula UEFG, where U is isocyanate, isothiocyanate or trichloromethylcarbonylamino. Formula IV

[0053]

Embedded image A urea or thiourea derivative of (wherein V is oxygen or sulfur) is obtained. By heating this derivative with acid to hydrolyze the ester functionality,
Type

Embedded image Cyclized to a compound of formula I

An example of another process for preparing compounds of formula I where Y is C = O or C = S and W is R ¹ -A-B-D-C (R ¹⁶ ) is formula V

Embedded image Reaction of compounds with phosgene, thiophosgene or equivalent (S. Goldschmidt and M. Wick, Liebigs A
nn. Chem. 575 (1952), 217-231 and C. Tropp, Chem.
Ber. 61 (1928), 1431-1439).

[0055]

Embedded image Type

Embedded image Where Y is C = O or C = S and W is R ¹
Compounds of formula I wherein heterocycle -A-B-D-C ( R 16) = a C), for example, be prepared by the following Scheme 1.

[0056]

Embedded image The conversion of the compound of formula VI into the compound of formula VII and the conversion of the compound of formula VII into the compound of formula VIII are described, for example, in S. Chung-gi.
Et al., Tetrahedron Lett 1987, 28 (33), 3827 or U. Sc.
Hmidt et al., Angew. Chemie 1984, 53.

Another option for preparing compounds of formula VIII is, for example, the compound of formula VII which is first cyclized under the influence of an acid to form compound of formula XII

Embedded image To form a compound of formula XII
In the ner-Emmons reaction, R ¹ -A-B-D-C (R ¹⁶ ) =
Consisting of reacting with O to form a compound of formula VIII.

Embedded image Type

Embedded image (Where W is

Embedded image A compound of formula I which is a heterocycle of) can be prepared, for example, by scheme 2 below.

[0058]

Embedded image In the formula, Q is a nucleophilically displaceable leaving group such as halogen, mesylate, tosylate and the like.

Conversion of a compound of formula IX to a compound of formula X is
For example, E. Marinez et al., Helv. Chim. Acta 1983, 66.
(1), 338 or EW Logusch et al., J. Org. Chem. 1988,
This can be done in the same way as 53 (17), 4069.

Embedded image Type

Embedded image Where Y is C = O or C = S and W is

Embedded image A compound of formula I which is a heterocycle of

[0060]

Embedded image

Another option for preparing compounds of formula XIII is, for example, cyclization of a compound of formula VII under the influence of acid to form a compound of formula XII and then a compound of formula XII,
In the Horner-Emmons reaction

Embedded image Reacting to form a compound of formula XIII.

However, during the transformation synthesis, depending on the meaning of the individual substituents R ¹ , A, B, D etc., first of all a heterocyclic ring system with only a few substituents is assembled and then for example a fragment bond. It may be advantageous to introduce the remaining substitutions therein. Example 1 as an example
The synthesis of the compound can be mentioned.

[0063]

Embedded image However, this general principle is not limited to this one example and is generally applicable.

R ¹ -A is

Embedded image Or type

Embedded image Compounds of formula I which are cyclic guanylhydrazones of, for example, N
i et al., Arch. Pharm. 325 (1992) 773-777 or A. Alves
Et al., Eur. J. Med. Chem. Chim. Ther. 21 (1986) 297-304.
Similarly, for example

Embedded image Type O = C (R ²⁾ - is a ketone or aldehyde or corresponding acetals or ketals and produced by condensing.

Where appropriate, the above guanylhydrazones can be obtained as a mixture of E / Z isomers.
This mixture of isomers can be resolved using chromatographic methods commonly practiced today.

R ¹ -A is RC (= NR ² ) NR ² -N = C
(R ² ) — or a type containing a monocycle or polycycle

Embedded image The compounds of formula I which are systems of can be obtained in a similar manner.

A compound of formula I wherein R ¹⁰ is SO ₂ R ¹¹ is
For example in the literature (eg Houben-Weyl, Methoden der Organi
schen Chemie, Vol. E 12/2, Georg Thieme Verlag, St
uttgart 1985, p. 1058ff).
A compound of formula I wherein ¹⁰ is SH and R ¹⁰ is SO ₃
It is prepared by obtaining a compound of formula I which is H.
Then, R ¹⁰ is converted to SO ₂ by esterification or an amide bond directly or via a corresponding sulfonic acid halide.
A compound of formula I is obtained in which R ¹¹ (R ¹¹ ≠ OH). If necessary, oxidation-sensitive groups in the molecule, eg amino, amidino or guanidino groups, are protected with suitable protecting groups before carrying out the oxidation.

The compound of formula I wherein R ¹⁰ is S (O) R ¹¹ is
For example, compounds of formula I in which R ¹⁰ is SH are converted to the corresponding sulfides (R ¹⁰ is S ⁻ ) and then oxidized with meta-chloroperbenzoic acid to give sulfinic acid (R ¹⁰
Is SO ₂ H) (Houben-Weyl, Methoden der Organischen Chemie,
Vol. E 11/1, Georg Thieme Verlag, Stuttgart 1985,
p. 618 ff). The corresponding sulfinic acid esters or amides (R ¹⁰ is S (O) R ¹¹ (R ¹¹ ≠ OH)) can be prepared from this acid using methods known from the literature. In general, the literature (Houben-Weyl, Methoden der Organischen Chem) for preparing compounds of formula I in which R ¹⁰ is S (O) _n R ¹¹ (n is 1 or 2).
ie, Vol.E 11/1, Georg Thieme Verlag, Stuttgart 198
5, p. 618 ff or Vol. E 11/2, Stuttgart 1985, p. 1
Other methods known from (see 055 ff) can also be used.

Compounds of formula I in which R ¹⁰ is P (O) R ¹¹ _n (n is 1 or 2) are described in the literature (Houben-Weyl, Metho
den der Organischen Chemie, Vols. E 1 and E 2, Geo
rg Thieme Verlag, see Stuttgart 1982) and synthesized from a suitable precursor. A synthetic method suitable for the target molecule is selected.

A compound of formula I wherein R ¹⁰ is C (S) R ¹¹ is
References (Houben-Weyl, Methoden derOrganischen Chemie,
Vol. E 5/1 and E 5/2, Georg Thieme Verlag, Stuttg
It can be produced using a method known from art 1985).

R ¹⁰ is S (O) _n R ¹¹ (n is 1 or 2), P (O) R ¹¹ _n (n is 1 or 2) or C
Compounds of formula I which are (S) R ¹¹ may also be prepared by fragment linkage as described above. This process is for example carried out when E-F-G of formula I contains for example (commercially available) aminosulfonic acid, aminosulfinic acid, aminophosphonic acid or aminophosphinic acid or a derivative thereof such as an ester or an amide, It is advantageous.

R ¹ -A is R ² R ³ N-C (= NR ² ) -N
(R ² ) -C (O)-or type

Embedded image The compounds of formula I is a cyclic acyl guanidine, e.g. W is Q (O) C-B- D-C (R 16) - or Q (O) C-B
-DC (R ¹⁶ ) = C or

Embedded image And Q is a leaving group that can be readily nucleophilically displaced.

Embedded image The corresponding guanidine (derivative) or form of

Embedded image It can be produced by reacting with a cyclic guanidine (derivative).

Type Q (O) C (wherein Q is an alkoxy group, preferably a methoxy group, a phenoxy group, a phenylthio group,
A methylthio group, a 2-pyridylthio group or a nitrogen heterocycle,
Said activated acid derivative of preferably 1-imidazolyl) is advantageously obtained in a manner known per se from the underlying carbonyl chloride (Q is Cl). The latter compounds can be prepared in a manner known per se, for example using thionyl chloride from the basic carboxylic acid (Q is OH).

Carbonyl chloride (Q is Cl)
Besides, other activated acid derivatives of the type Q (O) C- can also be prepared in a manner known per se in the known carboxylic acid (Q
Is OH). For example, the methyl ester (Q is OCH ₃ ) is obtained by treatment with gaseous HCl in methanol,
Imidazolide (Q is 1-imidazolyl) is obtained by treatment with carbonyldiimidazole [St
aab, Angew. Chem. Int. Ed. Engl. 1, 351-367 (1962)
Reference] and mixed anhydrides (Q is C ₂ H ₅ OC (O) O or TosO) were obtained using Cl-COOC ₂ H ₅ or tosyl chloride respectively in the presence of triethylamine in an inert solvent. To be Carboxylic acids also include dicyclohexylcarbodiimide (DCCI) or O-[(cyano (ethoxycarbonyl) methylene) amino] -1,
1,3,3-Tetramethyluronium-tetrafluoroborate (“TOTU”) [Weiss and Krommer, Chemike
r Zeitung 98, 817 (1974)] and other activating reagents commonly used in peptide chemistry. A series of suitable methods for preparing activated carboxylic acid derivatives of formula II are described in J. March, Advanced Organic C
hemistry, Third Edition (John Wiley & Sons, 1985),
See p. 350.

The reaction of the activated carboxylic acid derivative of type Q (O) C- with the respective guanidine (derivative) is carried out in a manner known per se in a protic or aprotic polar inert organic solvent. Done. In this context, methanol, isopropanol or THF at temperatures between 20 ° C. and the boiling temperature of the solvent proved valuable when reacting the methyl ester (Q is OMe) with the respective guanidine. Most reactions of compounds of type Q (O) C- with non-salt guanidine are advantageously carried out in aprotic, inert solvents such as THF, dimethoxyethane and dioxane. However, if a base (eg NaOH) is used, the water is also Q (O) C.
-Can be used as a solvent when reacting with guanidine.

When Q is Cl, the reaction is advantageously carried out in the presence of an acid scavenger for the purpose of binding and removing hydrohalic acids, eg in the form of excess guanidine (derivative). .

R ¹ -A is R ² -C (= NR) -N (R ² ) -C
(O) -or monocyclic or polycyclic containing type

Embedded image The compounds of formula I which are systems of can be obtained in a similar manner.

R ¹ -A is of the type R ² R ³ N-C (= NR ² ) -N
R ² —S (O) _n (where n is 1 or 2) or

Embedded image Compounds of formula I which are sulfonylguanidines or sulfoxylguanidines, where n is 1 or 2, can be prepared using methods known from the literature using S. Birtwell et al.
J. Chem. Soc. (1946) 491 or Houben Weyl, Methoden
der Organischen Chemie, Vol. E 4, Glorg Thieme Ver
lag, Stuttgart 1983, p. 620 ff, R ² R ³ N-
C (= NR ² ) NR ² H or

Embedded image The W is _{Q-S (O) n -B} -D-C (R 16) - or Q-S
_{(O) n -B-D-} C (R 16) = C or

Embedded image And Q is, for example, Cl or NH ₂ prepared by reacting with a sulfinic acid derivative or a sulfonic acid derivative of formula I.

R ¹ -A is R ² -C (= NR ² ) NR ² -S
(O) _n (n is 1 or 2) or a monocyclic or polycyclic type

Embedded image The compounds of formula I, which are systems of the formula (where n is 1 or 2) can be obtained in a similar manner.

A is --NR ² --C (O)-NR ² , --NR ^2-
C (O) O-or -NR ² -C (O) a S- and R ¹
Is R ² R ³ NC (= NR ² ), R ² -C (= NR ² ), or as described above and optionally substituted 4 to 4 above.
Compounds of formula I which are 14-membered mono- or polycyclic aromatic or non-aromatic ring systems include, for example, first of all, where W is Q-
^{B-D-C (R 16} ) - or Q-B-D-C ( R 16) = C or

Embedded image And Q is HNR ² —, HO or HS—, depending on the carbonic acid derivative used, −2
Temperatures between 0 ° C and the boiling point of the solvent, preferably 0 ° C and 60
A suitable carbonic acid derivative, preferably phosgene, diphosgene (trichloromethyl chloroformate), triphosgene (in Bis (trichloromethyl) carbonate), ethyl chloroformate, i-butyl chloroformate, bis- (1-hydroxy-1-H-benzotriazol) carbonate or N,
When reacted with N'-carbonyldiimidazole, W

Embedded image And R is —NR ² —, —O— or —S— and Q ′ is chlorine, ethoxy, isobutoxy, benzotriazole-1-oxy or 1-imidazolyl. Manufactured by forming.

These derivatives and R ² R ³ NC (= NR ² )
-NR ² H, or ^{R 2 -C (= NR 2)} -NR 2 H , or molds containing monocyclic or polycyclic

Embedded image The reaction with the system is carried out as described above in connection with the production of the acylguanidine (derivative).

F is R ² N—C (O) —NR ² or R ² N—
Compounds of formula I which are C (S) -NR ² can be prepared, for example, using methods known from the literature.

Embedded image Prepared by reacting a compound of 1 with an isocyanate OCN-G or an isothiocyanate SCN-G.

Compounds of formula I in which F is C (O) NR ² , --SO ₂ NR ² --or --C (O) O-- can be prepared by methods known from the literature, for example by:

Embedded image (Q is a leaving group that can be easily displaced nucleophilically such as OH, Cl, OMe, etc.) can be obtained by reacting with HR ² N-G or HO-G.

R ¹ -A is a type

Embedded image Compounds of formula I consisting of mono- or polycycles of, for example, the compounds of the literature [eg AF Mckay et al., J. Med. Chem.
N. Buchman et al., J. Am. Chem. Soc. 71 (1949), 766, F.
Jung et al., J. Med. Chem. 34 (1991) 1110 or G. Sorba.
Et al., Eur. J. Med. Chem. 21 (1986), 391], W is HR ² N-B-D-C (R
¹⁶ )-or HR ² N-B-D-C (R ¹⁶ ) = C or

Embedded image A compound of formula I which is

Embedded image (In the formula, X is halogen, SH, SCH ₃ , SOC
Can be prepared by reacting _{H 3, SO 2 CH 3,} SO 3 is a leaving group capable of nucleophilic substitution, such as H or HN-NO ₂₎ monocyclic or polycyclic .

R ¹ -A is a mold

Embedded image Compounds of formula I consisting of mono- or polycyclic compounds of the formula I are described, for example, in the literature [e.g.
Purkayastha et al., Indian J. Chem. Sect. B30 (1991) 64.
6] is used, W is HR ² N-B
-D-C (R ¹⁶⁾ - or ^{HR 2 N-B-D-} C (R 16) =
C or

Embedded image A compound of formula I which is

Embedded image It can be produced by reacting with a compound of the formula (X is a leaving group such as —SCH ₃ ).

Compounds of formula I in which R ¹ -A is a bis-aminotriazole or bis-aminooxadiazole group are described, for example, by PJ Garrett et al., Tetrahedron 49 (1993) 165.
Or R. Lee Webb et al., J. Heterocyclic Chem. 24 (198
7) It can be prepared by the following reaction sequence as described in 275.

[0087]

Embedded image Production methods known from the literature are, for example, J. March,
Advanced Organic Chemistry, Third Edition (John Wil
ey & Sons, 1985).

The compounds of the formula I and the physiologically acceptable salts of these compounds allow the use alone or as a mixture with one another or for the enteral or parenteral use and are customary pharmaceutically problem-free carriers. It may be administered as a pharmaceutical to an animal, preferably a mammal, especially a human in the form of a pharmaceutical preparation containing, in addition to the substances and auxiliary substances, an effective amount of at least one compound of the compound of formula I or a salt thereof as active ingredient. it can. The formulations usually contain about 0.5 to 90% by weight of the therapeutically active substance.

The medicaments can be administered orally, for example in the form of pills, tablets, lacquer tablets, coated tablets, granules, hard gelatin capsules, hard gelatin capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. . However, the administration can also be rectally, for example in the form of suppositories, parenterally, for example in the form of injectable solutions, infusion solutions, microcapsules or rods, transdermally, for example in the form of ointments or tinctures, or It can be administered nasally in the form of a nasal spray.

The pharmaceutical preparations are prepared in a manner known per se using pharmaceutically inert, inorganic or organic carrier substances. For example, lactose, corn starch or a derivative thereof, talc, stearic acid or a salt thereof,
It can be used for the production of pills, tablets, coated tablets and hard gelatin capsules. Examples of carrier materials for soft gelatin capsules and suppositories are fats, waxes, semisolid and liquid polyols, natural or hardened oils and the like. Examples of suitable carrier materials for the production of solutions and syrups are water, sucrose, invert sugar, glucose, polyols and the like. Suitable carrier materials for preparing injectable solutions are water, alcohols, glycerol,
Examples include polyols and vegetable oils. Suitable carrier materials for microcapsules, implants or rods are mixed polymers of glycolic acid and lactic acid.

In addition to the active compounds and carrier substances, the pharmaceutical preparations also include fillers, fillers, disintegrants, binders, glidants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, dyes,
Flavoring or flavoring agents, thickening agents, diluents and buffering substances, and also additives such as osmotic pressure-changing salts, coatings or antioxidants can be included. The pharmaceutical preparation may contain two or more compounds of the compound of formula I or physiologically acceptable salts thereof. The pharmaceutical preparation may further contain, in addition to at least one compound of formula I, one or more different therapeutically active compounds.

The dosage can vary within wide limits and must be adjusted to the individual circumstances in each individual case.

In the case of oral administration, the daily dose is 0.01 to 50 mg / kg, preferably 0.1 to 5 mg / kg, preferably 0, kg / kg body weight in order to achieve effective results. It is 0.3 to 0.5 mg / kg. On the other hand, in the case of intravenous administration, the daily dose is generally about 0.01 to 100 mg / kg of body weight, preferably 0.0.
It is 5-10 mg / kg. If you administer a relatively large amount,
The daily dose can be divided into several, for example 2, 3 or 4, doses. Depending on the individual response, it may be necessary to escalate the daily dose upwards or downwards, as appropriate.

[0094]

EXAMPLES The products are mass spectra and / or
Characterized by NMR spectrum.

Example 1 (2S) -Benzoylcarbonylamino-3- [2-((4
S)-(3- (4,5-dihydro-1H-imidazole-
2-ylamino) propyl) -2,5-dioxoimidazolidin-1-yl) acetylamino] propionic acid (1.8)

Embedded image The synthesis was performed according to the following reaction sequence.

Embedded image 1a) (2S) -2-Amino-5-benzyloxycarbonylaminopentanoic acid methyl hydrochloride (1.2) 240 ml of thionyl chloride are added dropwise to 300 ml of anhydrous methanol under ice cooling and under an argon atmosphere, Thereafter, (2S) -2-amino-5-benzyloxycarbonylaminopentanoic acid (1.1) 40 g (150
Mmol) and the mixture is reacted at room temperature for 3 hours and at 4 ° C. overnight. The solution is poured onto methyl tert-butyl ether, the solvent is decanted off and the residue is triturated with diethyl ether. After filtering off with suction, (1.
2) 29.14 g (61%) was obtained as a colorless solid. 1b) 5-benzyloxycarbonylamino- (2
Methyl S)-(3-ethoxycarbonylmethylurea) pentanoate (1.3) at 0 ° C. and with stirring 3.83 g (29.7 mmol) ethyl isocyanate ethyl acetate and then 3 g (29.7 mmol) triethylamine. , A solution of 9.41 g (29.7 mmol) of compound (1.2) in 150 ml of dichloromethane / tetrahydrofuran (2: 1) are added dropwise. After 30 minutes at 0 ° C., the ice bath is removed and the reaction mixture is stirred at room temperature for a further 1.5 hours. After removing the solvent in vacuo, the residue is chromatographed on silica gel using ethyl acetate. The product fractions are concentrated and the residue is triturated with ether and filtered off with suction. (1.3) 11.02 g (83
%) Was obtained as a colorless solid.

1c) [(4S)-(3-Aminopropyl) -2,5-dioxoimidazolidin-1-yl] acetic acid hydrochloride (1.4) (1.3) 10.4 g (42.9) Is heated to reflux with 100 ml of 6N hydrochloric acid for 45 minutes. Concentrate the solution,
Water is added to the residue and the whole is freeze-dried. (1.
4) 7.1 g (66%) was obtained as a colorless solid. 1d) [(4S)-(3- (4,5-dihydro-1H
-Imidazol-2-ylamino) propyl) -2,5
-Dioxoimidazolidin-1-yl] acetic acid hydrochloride (1.5) (1.4) 400 mg (1.59 mmol) and 2- (methylmercapto) -2-imidazoline hydrochloride 388 mg
(1.59 mmol) is dissolved in 5 ml H ₂ O. The mixture was adjusted to pH 9 with 1N NaOH and 1N NaOH
60 ° C while maintaining the pH of the solution at 9 by adding
Heat for 2.5 hours (total consumption of 1N NaOH: 3.4 m
l). The reaction mixture was left at room temperature for 3 days and the pH was adjusted to 1N HC.
Adjusted to 1 with l, the solvent is removed in vacuo and the residue is chromatographed on silica gel using MeOH / H ₂ O = 9/1. The product fraction is concentrated and lyophilized. (1.5) 230 mg
(45%) was obtained as a colorless powder.

1e) Tertiary butyl (2S) -3-amino-2-benzyloxycarbonylaminopropionate (1.6) 10 g (42 mmol) of (2S) -3-amino-2-benzyloxycarbonylaminopropionic acid 100 ml of dioxane, 100 ml of isobutylene and concentrated H ₂ SO ₄
In a mixture of 8 ml, shake in an autoclave under N ₂ pressure of 20 atm for 3 days. The excess isobutylene is blown off and 150 ml of diethyl ether and 150 ml of a saturated solution of a saturated solution of NaHCO ₃ are added to the residual solution. The phases are separated and the aqueous phase is extracted twice with 100 ml of diethyl ether in each case. The combined organic phases are washed with 2 × 100 ml H ₂ O and dried over Na ₂ SO ₄ . After removing the solvent in vacuo, 9.58 g (78%) of (1.6) was obtained as a pale yellow oil. 1f) (2S) -benzyloxycarbonylamino-
3- [2-((4S)-(3- (4,5-dihydro-1H-
Imidazol-2-ylamino) propyl) -2,5-
Dioxoimidazolidin-1-yl) acetylamino]
Tertiary butyl propionate (1.7) (1.5) 200 mg (0.7 mmol) and HOOBt
114 mg (0.7 mmol) are suspended in 5 ml DMF and 154 mg DCCI (0.7 mmol) are added at 0 ° C. The mixture was stirred at 0 ° C. for 1 hour and at RT for 1 hour and then 206 mg (0.7 mmol) (1.6).
Is added, the mixture is stirred at RT for 2 h and left at RT overnight. The solvent was removed in vacuo and the residue was dichloromethane / methanol / glacial acetic acid / water = 8/2 / 0.2
Chromatography on silica gel using /0.2. After concentration and freeze-drying, (1.7) 105 mg
(27%) was obtained as a colorless solid. 1 g) (2S) -benzyloxycarbonylamino-
3- [2-((4S)-(3- (4,5-dihydro-1H-
Imidazol-2-ylamino) propyl) -2,5-
Dioxoimidazolidin-1-yl) -acetylamino] propionic acid (1.8) (1.7) 105 mg (0.188 mmol), 90% trifluoroacetic acid 2 ml and 1,2-dimercaptoethane 0.1. Dissolve in 2 ml of homogeneous solution and bring the solution to RT 1
Leave for a time. After concentrating in vacuo, the residue is partitioned between diethyl ether and water and the aqueous phase is freeze dried. H ₂ O / n-butanol /HOAc=43/4.3
/3.5 was chromatographed and then lyophilized on Sephadex ^R LH20 using,
Obtained 45 mg (48%) of (1.8) as a colorless solid.

Example 2 3- [2-((4S)-(3- (5-amino-2H- [1.
2.4] triazol-3-ylamino) propyl) -2,
5-Dioxoimidazolidin-1-yl) acetylamino]-(2S) -benzyloxycarbonylaminopropionic acid (2.5)

Embedded image The synthesis was performed according to the following reaction sequence.

Embedded image 2a) [(4S)-(3-tert-butoxycarbonylaminopropyl) -2,5-dioxoimidazolidine-1-
Yl] acetic acid (2.1) (1.4) 6 g (23.84 mmol) in THF / H ₂
It is dissolved in 350 ml of O = 2/1. The pH of the solution was adjusted to 10.5 with 1N NaOH at 0 ° C., 6.24 g (28.61 mmol) di-tert-butyldicarbonate was added and the pH of the solution was adjusted to 9 and 10.5 by addition of 1N NaOH. Keep between and. The solution was stirred at 0 ° C for 1 hour and 4 ° C
Leave it overnight. The pH is adjusted to 4 with phosphate buffer and the solvent removed in vacuo. Triturate the residue in methanol and filter the mixture and concentrate the filtrate. Dichloromethane / MeOH / glacial acetic acid / water = 7 /
After chromatography on silica gel using 3 / 0.3 / 0.3, a (2.1) viscous syrup was obtained. 2b) (2S) -benzyloxycarbonylamino-
Tertiary butyl 3- (2-((4S)-(3-tert-butoxycarbonylaminopropyl) -2,5-dioxoimidazolidin-yl) acetylamino] propionate (2.
2) (2.1) 2.8 g (8.9 mmol) and HOOBt
1.45 g (8.9 mmol) were dissolved in 50 ml DMF and 1.95 g DCCI (8.9 mmol) at 0 ° C.
Add in. After 1 hour at 0 ° C and 1 hour at RT,
2.6 g (8.9 mmol) of (1.6) are added and the reaction mixture is stirred at RT for 2 hours and left at RT overnight. After filtration, the filtrate is concentrated and the residue is partitioned between H ₂ O and ethyl acetate, the organic phase is dried over Na ₂ SO ₄ , the solvent is removed in vacuo and the residue is taken up in acetic acid. Chromatography on silica gel with ethyl / heptane (9/1 to 6/4) gives (2.2) 2.98 g.
(57%) was obtained.

2c) 3- [2-((4S)-(3-aminopropyl) -2,5-dioxoimidazolidine-1-
Yl) acetylamino]-(2S) -benzyloxycarbonylaminopropionic acid (2.3) (2.2) 2.9 g (4.9 mmol), dichloromethane 20 ml, trifluoroacetic acid 9.8 ml and triethylamine 2. Dissolve in a mixture of 35 ml. At RT 3.
After 5 hours, the mixture is concentrated and then freeze-dried. The residue is triturated in diethyl ether, dried, crystallized in a small amount of methanol and triturated with ether. 1.34 g (50%) of (2.3) was obtained as a colorless solid. 2d) 3- [2-((4S) -4- (3- (phenoxy-
N-cyanoiminocarbonylamino) propyl) -2,5
-Dioxoimidazolidin-1-yl) acetylamino]-(2S) -benzyloxycarbonylaminopropionic acid (2.4) (2.3) 400 mg (0.73 mmol) was added to DMF 10
Dissolve in ml. 0.14 ml triethylamine then DM
190.7 mg of diphenyl cyanocarbamate in 2 ml of F
(0.8 mmol) is added. After stirring the mixture for 2 hours at RT, the solvent was removed in vacuo and the residue was dissolved in 50 ml of a 5% solution of acetic acid and the solution was freeze-dried. After chromatography on silica gel using methanol, 260 mg (61%) of (2.4) was obtained. 2e) 3- [2-((4S)-(3- (5-amino-2N
-[1.2.4] triazol-3-ylamino) propyl) -2,5-dioxoimidazolidin-1-yl) acetylamino]-(2S) -benzyloxycarbonylaminopropionic acid (2.5) ( 2.4) 260 mg (0.45 mmol) are suspended in 10 ml isopropanol and 62.4 μl (0.45 mmol) triethylamine are added. 28.5 μl (0.585 mmol) hydrazine are added and the mixture is heated to reflux for 10 hours. Then it is left at RT overnight, after which the precipitate is filtered off with suction and butanol, T
Wash with HF and ether. Use H ₂ O / n-butanol /HOAc=43/4.3/3.5 after chromatography on Sephadex ^R LH 20, the (2.5) 80mg (34%) , colorless Obtained as a solid.

Example 3 (2S) -Benzyloxycarbonylamino-3-
[((4S)-(guanidinoacylaminomethyl) -2,5
-Dioxoimidazolidin-1-yl) acetylamino] propionic acid (3.11) The synthesis was carried out by the following reaction sequence.

Embedded image 3a) (2S), Methyl didiaminopropionate dihydrochloride (3.2) 35 ml of thionyl chloride are added dropwise to 60 ml of anhydrous methanol at -15 ° C and under an argon atmosphere, after which
(2S), 3-diaminopropionate hydrochloride (3.1) 2
5 g (240 mmol) and 100 more methanol
Add ml. After stirring for 16 hours at room temperature, the mixture is mixed with 4
Heat to reflux for hours. The solution is poured into diisopropyl ether, the solvent is decanted off and the residue is chromatographed on silica gel using methanol.
The product fractions are concentrated and the residue is triturated with diisopropyl ether. After filtering off the precipitate with suction and drying on paraffin, 26.3 g of (3.2)
(57%) was obtained as a pale yellow solid. 3b) (2S) -Amino-3-tert-butoxycarbonylaminopropionate methyl hydrochloride (3.3) 75.8 ml of triethylamine at -78 ° C, 26 g of (3.2) in 4.4 liters of dichloromethane ( 220 mmol), followed by dichloromethane 220
26.78 g of di-tert-butyl dicarbonate (12
3 mmol) solution is added dropwise, the mixture is warmed to 0 ° C. and then stirred at this temperature for 1.5 h. The reaction mixture is concentrated and the residue is chromatographed on silica gel using ethyl acetate / methanol = 20/1. 15.73 g (58%) of (3.3) was obtained as a pale yellow syrup.

3c) (2S) -Ethyloxycarbonylmethylaminocarbonylamino-3-tert-butoxycarbonylaminomethylpropionate (3.4) 5.13 ml (45.8 mmol) of ethyl acetate isocyanate were dissolved in 100 ml of tetrahydrofuran. Compound (3.
3) 10 g (45.8 mmol) suspension was added dropwise and the mixture was stirred at room temperature for 3 hours, the solvent was removed in vacuo and the residue was taken up with ethyl acetate / methanol = 20/1. Chromatography on silica gel.
13.44 g (85%) of (3.4) were obtained as a pale yellow oil. 3d) 2-[(4S)-(aminomethyl) -2,5-dioxoimidazolidine] acetic acid hydrochloride (3.5) (3.4) 13.2 g (34 mmol) of 6N hydrochloric acid 150
Heat to reflux with ml for 45 minutes. The solution is concentrated and the residue is lyophilized. Dichloromethane / methanol = 7
Chromatography on silica gel using / 3 and lyophilization of the product fractions (3.
5) 6.4 g (84%) was obtained as a colorless solid.

3e) 2-[(4S)-(tertiary butoxycarbonylaminomethyl) -2,5-dioxoimidazolidine] acetic acid (3.6) 1N NaOH at 0 ° C. until a pH of 10.5 was reached. And tetrahydrofuran / water = 2/1 in 300 ml (3.5)
Added to a solution of 4.4 g (19.7 mmol) (consumption: 26
ml), di-tert-butyl dicarbonate 5.16 g (23.6
Mmol) and the pH is maintained between 9.5 and 10.5 by the addition of 1N NaOH. After 1 hour at 0 ° C. and 2 hours at room temperature, the mixture is left overnight at 4 ° C., then the pH is adjusted to 7 with 1N HCl and then to 4.1 with phosphate buffer. The solvent was removed in vacuo and the residue was triturated with methanol, the mixture was filtered and the filtrate was concentrated and the residue was
Dichloromethane / methanol / acetic acid / water = 8/2/0.
Chromatograph on silica gel using 2 / 0.2. The product fraction is concentrated and lyophilized. Yield of (3.6): 3.6 g (64%). Colorless solid. 3f) Methyl 3-amino- (2S) -benzyloxycarbonylaminopropionate hydrochloride (3.7) 7.4 ml (100.8 mmol) of thionyl chloride was added at -15 ° C.
In 50 ml of anhydrous methanol are added dropwise. 12 g (50.4 mmol) 3-amino- (2S) -benzyloxycarbonylaminopropionate hydrochloride and then 40 ml anhydrous methanol are added. After stirring for 45 minutes at −15 ° C. and 20 hours at room temperature, the reaction mixture is poured into diisopropyl ether and the precipitate is filtered off with suction and dried under high vacuum. 14.18 g (98%) of (3.7) was obtained as a colorless solid.

3g) (2S) -Benzyloxycarbonylamino-3-[((4S)-(tertiary butoxycarbonylaminomethyl) -2,5-dioxoimidazolidine-
Methyl 1-yl) acetylamino] propionate (3.
8) HOOBt 848 mg (5.2 mmol) and then DCCI 1.144 g (5.2 mmol) at 0 ° C.
And 1.5 g (5.2) of (3.6) in 20 ml of anhydrous DMF.
Mmol) solution. After stirring for 1 hour at 0 ° C. and 1 hour at room temperature, 1.5 g (5.2 mmol) (3.7) and 0.67 ml N-ethylmorpholine are added and the mixture is stirred for 3 hours at room temperature. The precipitate is filtered off and the filtrate is concentrated, the residue is taken up in ethyl acetate and this solution is, in turn, a saturated solution of NaHCO ₃ , KHSO ₄ / K.
Wash with ₂ SO ₄ solution and water, and dry the organic phase over sodium sulfate. After filtration and removal of the solvent in vacuo, the residue is chromatographed on silica gel using ethyl acetate / heptane = 6 / 4-ethyl acetate and (3.8) gives 1.75 g (65%). It was 3h) 3-[((4S)-(aminomethyl) -2,5-dioxoimidazolidin-1-yl) -acetylamino]
1.7 g (3.26 mmol) of-(2S) -benzyloxycarbonylaminopropionic acid methyl trifluoroacetate (3.9) (3.8) was added to dichloromethane 6.7 ml, trifluoroacetic acid 3.3 ml and triethyl. Stir for 4 hours at room temperature in 0.78 ml of silane. The solution is poured into diethyl ether and the precipitate is filtered off. 1.54 g (88%) of (3.9) was obtained as a colorless solid.

3i) (2S) -Benzyloxycarbonylamino-3-[((4S)-(guanidinoacylamino-methyl) -2,5-dioxoimidazolidine-1-
(Aryl) acetylamino] methyl propionate (3.1
0) 0.12 ml of triethylamine is added to a solution of 500 mg (3.93 mmol) of (3.9) in 10 ml of anhydrous DMF, followed by the addition of 152 mg (0.93 mmol) of carbonyldiimidazole in 10 ml of anhydrous DMF. Solution at 0 ℃
Add in. After stirring at room temperature for 4 hours, guanidine 89
mg (1.86 mmol) was added and the mixture was stirred at room temperature for 2 hours, then the solvent was removed in vacuo and the residue was dichloromethane / methanol / acetic acid / water = 8.5 /
Chromatography on silica gel using 1.5 / 0.15 / 0.15. After concentrating the product fractions and freeze-drying, (3.10) 300 mg (64%)
Was obtained as a colorless solid. 3j) (2S) -benzyloxycarbonylamino-
3-[((4S)-(guanidinoacylaminomethyl)-
2,5-Dioxoimidazolidin-1-yl) acetylamino] propionic acid (3.11) (3.10) 180 mg (0.32 mmol) dioxane /
It dissolves in a mixture consisting of water / triethylamine = 1/1/1. After 16 hours at room temperature, the mixture is subjected to rotary evaporation, after which the residue is treated with water and lyophilized. The residue from lyophilization is chromatographed on silica gel using dichloromethane / methanol / acetic acid / water = 8/2 / 0.2 / 0.2. The product fraction is subjected to rotary evaporation and the residue is treated with water and freeze dried. The residue from this lyophilization is then triturated with ethyl acetate and diethyl ether. After filtering off with suction, 62 mg (39%) of (3.11)
Obtained as a colorless solid. ES (+)-MS: 493 (M + H) ⁺

Example 4 (2S) -Benzyloxycarbonylamino-3-
[((4S)-(3- (2-pyridylamino) propyl)
-2,5-Dioxoimidazolidin-1-yl) acetylamino] propionic acid (4.2) The synthesis was carried out by the following reaction sequence.

Embedded image 4a) 2-[(4S)-(3-pyrimidylamino) propyl) -2,5-dioxoimidazolidine] acetic acid (4.
1) A mixture of 1 g (4 mmol) (1.4), 632 mg 2-bromopyrimidine (4 mmol) and 2.04 ml (12 mmol) diisopropylethylamine (DIPEA) in 9 ml DMF is heated at 80 ° C. for 26 hours. . The solvent is removed in vacuo and the residue is chromatographed on silica gel using dichloromethane / methanol / acetic acid / water = 8/2 / 0.2 / 0.2. The product fraction was concentrated and (4.1) 144 mg (12
%) Was obtained as a colorless solid. 4b) (2S) -benzyloxycarbonylamino-
3-[((4S)-(3- (2-pyrimidylamino) propyl) -2,5-dioxoimidazolidin-1-yl)
Acetylamino] tert-butylpropionate (4.2) DCCI 97 mg (0.44 mmol) was added to DMF 5 ml.
(4.1) 128 mg (0.44 mmol), (1.
6) 128 mg (0.44 mmol), HOBt 60 mg
(0.44 mmol) and N-ethylmorpholine 0.0
Add to 35 ml of solution. 1 hour at 0 ° C and 16 at room temperature
After time, the solvent was removed in vacuo and the residue was dichloromethane / methanol / acetic acid / water = 9.5 / 0.5 /
Chromatograph on silica gel using 0.05 / 0.05. (4.2) 180 mg (72%) were obtained. 4c) (2S) -benzyloxycarbonylamino-
3-[((4S)-(3- (2-pyrimidylamino) propyl) -2,5-dioxoimidazolidin-1-yl)
Acetylamino] propionic acid (4.3) (4.2) 170 mg (0.3 mmol), 90% trifluoroacetic acid 2 ml and 1,2-dimercaptoethane 0.2
Dissolve in a mixture of ml. After 1 hour at room temperature, the mixture was added diethyl ether and the precipitate was centrifuged,
Resuspend in diethyl ether and centrifuge again.
After dissolving in water and freeze-drying, the residue was chromatographed on Sephadex LH 20 using water / butanol / acetic acid = 43 / 4.3 / 3.5. After freeze-drying, 76 mg (49%) of (4.3) was obtained as a colorless solid. ES (+)-MS: 514 (M + H) ⁺

Example 5 (2S) -Benzyloxycarbonylamino-3-
[((4S)-(3- (Benzimidazolyl-2-amino) -propyl) -2,5-dioxoimidazolidine-
1-yl) acetylamino] propionic acid (5.5) The synthesis was carried out by the following reaction sequence.

Embedded image 5a) 2-[(4S)-(3- (3- (2-nitrophenyl) thioureido) propyl) -2,5-dioxo-imidazolidin-1-yl] acetic acid (5.1) 4.96 ml triethylamine ( 35.76 mmol) and then 2-nitrophenyl isothiocyanate 3.2
2 g (17.88 mmol) DMF 100 ml at 0 ° C
To a solution of 4.5 g (17.88 mmol) of (1.4) in. After stirring for 4 hours at room temperature, the solvent is removed in vacuo and the residue is partitioned between dichloromethane and 10% acetic acid. The aqueous phase is extracted twice with dichloromethane and the organic phase is dried over sodium sulphate. After filtration, the solvent is removed in vacuo and the residue is chromatographed on silica gel. The product fraction was concentrated and 3.5.1 g (45%) of (5.1) was obtained. 5b) 2-[(4S)-(3- (3- (2-aminophenyl) thioureido) propyl) -2,5-dioxo-imidazolidin-1-yl] acetic acid (5.2) 10% Pd / C3. 0.8 g in 40 ml absolute ethanol (5.
1) Add to 4.6 g (11.6 mmol). 200 ml of ammonia-saturated ethanol are added and the mixture is hydrogenated at room temperature for 6 hours. The catalyst is filtered off, the filtrate is concentrated and the residue is used directly to synthesize (5.3).

5c) 2-[(4S)-(3- (Benzimidazolyl-2-amino) propyl) -2,5-dioxoimidazolidin-1-yl] acetic acid (5.3) (35) in 35 ml of ethanol ( 5.2) 1.85 g are heated under reflux with 3 g mercuric oxide and 730 mg sulfur for 16 hours. The mixture is filtered and the residue is leached with water 5 times. The combined aqueous phases are freeze-dried. (5.3) 814mg
(21% based on (5.1)) was obtained as a colorless solid. 5d) (2S) -benzyloxycarbonylamino-
3-[((4S)-(3- (benzimidazolyl-2-amino) propyl) -2,5-dioxoimidazolidine-
1-yl) acetylamino] propion tert-butyl (5.4) (5.4) from (4.1) and (1.6) to (4.2)
As described in Example 4 for the preparation of (5.
It is synthesized by reacting 3) with (1.6). The crude product is dichloromethane / methanol / acetic acid /
After chromatography on silica gel using water = 9/1 / 0.1 / 0.1 and then freeze-drying the product fraction from (5.3) 205 mg (0.56 mmol), 255 mg (75%) of (5.4) was obtained as a colorless solid. 5e) (2S) -benzyloxycarbonylamino-
3-[((4S)-(3- (Benzimidazolyl-2-amino) -propyl) -2,5-dioxoimidazolidin-1-yl) acetylamino] propionic acid (5.5) Compound (5. 4) 90% of 250 mg (0.41 mmol)
Stir in 3 ml of trifluoroacetic acid at room temperature for 1 hour. Trifluoroacetic acid is removed in vacuo and the residue is treated with water and freeze dried. The residue from lyophilization is chromatographed on Sephadex LH 20 using water / butanol / acetic acid = 43 / 4.3 / 3.5. After lyophilization, 155 mg (66%) of (5.5) was obtained as a colorless solid. ES (+)-MS: 552 (M + H) ⁺

Example 6 (2S) -Benzyloxycarbonylamino-3-
[((4S)-(3- (cis-3a, 4,5,6,7,7a-
Hexahydro-1H-benzimidazol-2-ylamino) propyl) -2,5-dioxoimidazolidine-
1-yl) acetylamino] propionic acid (6.4) The synthesis was carried out by the following reaction sequence.

Embedded image 6a) [(4S)-(3- (cis-3a, 4,5,6,7,
7a-Hexahydro-1H-benzimidazole-2-
Ilamino) -propyl) -2,5-dioxoimidazolidin-yl] acetic acid hydrochloride (6.2) 0.51 ml DIPEA and 6 drops water (6.1) (GD Hartmann et al., WO 95) in 6 ml DMF. / 3271
0, produced as described by page 115).
298 mg (1 mmol) and (1.4) 251 mg (1
Mmol) and the mixture at 100 ° C. for 2 min.
Stir for 4 hours. The solvent is removed in vacuo and the residue is dichloromethane / methanol / acetic acid / water = 9/1 /
Chromatography on silica gel using 0.1 / 0.1, then the combined product fractions are separated using Sephadex LH using water / butanol / acetic acid = 43 / 4.3 / 3.5. Chromatography on 20. The product fractions are combined and lyophilized. After conversion to the hydrochloride salt, 130 mg (35%) of (6.2) was obtained as a colorless solid. 6b) (2S) -benzyloxycarbonylamino-
3-[((4S)-(3- (cis-3a, 4,5,6,7,7a
-Hexahydro-1H-benzimidazol-2-ylamino) propyl) -2,5-dioxoimidazolidin-1-yl) acetylamino] propionic acid tert-butyl acetate (6.3) (6.3) is (4.1) and (1.6) to (4.
As described in Example 4 for the production of 2), (6.
It is synthesized by reacting 2) with (1.6). The crude product is converted into dichloromethane / methanol / acetic acid / water = 8/2 / 0.2 / 0.2 and then 9/1 /
After chromatography on silica gel using 0.1 / 0.1 and then lyophilization, (6.2) 1
30 mg (0.35 mmol) to (6.3) 45 mg (19
%) As a colorless solid.

6c) (2S) -benzyloxycarbonylamino-3-[((4S)-(3- (cis-3a, 4,
5,6,7,7a-Hexahydro-1H-benzimidazol-2-ylamino) propyl) -2,5-dioxo-imidazolidin-1-yl) acetylamino] propionic acid (6.4) (6.3) 40 mg (0.168 mmol) are stirred in 1 ml 90% trifluoroacetic acid at room temperature for 1 hour. Trifluoroacetic acid was removed in vacuo and the crude product was washed with RP 1
After purification by preparative HPLC through 8 and then lyophilizing the product fraction, (6.4) 13 mg
(14%) was obtained as a colorless solid. ES (+)-MS: 558 (M + H) ⁺

Example 7 (2S) -benzyloxycarbonylamino-3- [2
-((4S)-(N '-(4,5-dihydro-1H-imidazol-2-yl) -hydrazinocarbonylmethyl]
-2,5-Dioxoimidazolidin-1-yl) acetylamino] propionic acid (7.8) The synthesis was carried out by the following reaction sequence.

Embedded image 7a) 5.5 ml of (4S) -carboxymethyl-2,5-dioxoimidazolidine (7.1) 11.7N sodium hydroxide solution and 7.5 g (92.5 mmol) of potassium cyanate at 80 ° C. Then, with stirring, is added to a suspension of 10 g (75 mmol) L-aspartic acid in water.
For 1 hour, the pH was adjusted to 85 ° C in each case with concentrated H
Adjust to 7 by adding small amount of Cl (consumption: 1.5 ml). The pH of the reaction mixture is then adjusted to 5.
Adjust to 3.5 with 5 ml. Further 9.5 ml of concentrated HCl are added and the reaction solution is stirred at 85 ° C. for 2 hours and then left at room temperature for 18 hours. The precipitate is filtered off with suction,
Wash with a small amount of ice cold water and dry over P ₂ O ₅ . (7.
1) 8.49 g (72%) were obtained as a colorless solid. 7b) (4S) -methoxycarbonylmethyl-2,5-
Dioxoimidazolidine (7.2) 7.9 ml (107 mmol) of thionyl chloride and (7.
1) 8.47 g (53.5 mmol) are added to 70 ml of methanol at 15 ° C. and the reaction mixture is stirred at room temperature for 24 hours. Then the solution is poured into diethyl ether and the precipitate is filtered off with suction and washed with diethyl ether. After drying under high vacuum, (7.2) 5.12 g (56
%) As a colorless solid. After concentrating the ether phase and triturating the residue with diethyl ether and drying under high vacuum, an additional 2.79 g (30) of (7.2)
%) Was obtained.

7c) [(4S) -Methoxycarbonylmethyl-2,5-dioxoimidazolidine] -acetic acid tertiary
4 g (23.2 mmol) of butyl (7.3) (7.2) were treated with 20 ml of anhydrous DMF under ice cooling and under an argon atmosphere.
1.02 g of sodium hydride in 55 (55% strength in oil)
(23.2 mmol) in suspension. After the evolution of hydrogen has ceased, 4.53 g (23.2 mmol) of tert-butyl bromoacetate are added. After stirring for 1 hour at 0 ° C. and 2 hours at room temperature and standing overnight, the solvent is removed and the residue is chromatographed on silica gel using dichloromethane / methanol = 40/1. The product fractions are concentrated and the residue is triturated with diethyl ether. 4.23 g (63%) of (7.3) was obtained. 7d) [(4S) -methoxycarbonylmethyl-2,
4.2 g (14.67 mmol) of 5-dioxoimidazolidine! Acetic acid (7.4) (7.3) are dissolved in 50 ml of 90% trifluoroacetic acid. After stirring for 1 hour at room temperature, trifluoroacetic acid is removed in vacuo and the residue is lyophilized. (7.4) 3.17 g (94%) was obtained. 7e) (2S) -benzyloxycarbonylamino-
3-[((4S) -methoxycarbonylmethyl-2,5-
Dioxoimidazolidin-1-yl) acetylamino]
Tertiary butyl propionate (7.5) (7.5) was prepared from (4.1) and (1.6) to (4.
As described in Example 4 for the production of 2),
It is synthesized by reacting (7.4) with (1.6). The crude product is converted into dichloromethane / methanol = 20
1 and then 40/1 after chromatography on silica gel and concentration of the product fractions (7.4) from 1 g (4.3 mmol) to (7.5) 1.72 g (79%). ) Got.

7f) (2S) -benzyloxycarbonylamino-3-[((4S) -carboxymethyl-2,
Tert-Butyl 5-dioxoimidazolidin-1-yl) acetylamino] propionate (7.6) 700 mg (1.38 mmol) 700 mg (7.5) in water / dioxane / triethylamine = 1/1/1 50 ℃
Stir for 6 hours. After standing overnight at room temperature, the reaction mixture is concentrated and the residue is chromatographed on silica gel using dichloromethane / methanol / acetic acid / water = 9/1 / 0.1 / 0.1. After concentrating the product fractions, 7.6 mg (54%) of (7.6) was obtained. 7g) (2S) -benzyloxycarbonylamino-
3- [2-((4S)-(N '-(4,5-dihydro-1H
-Imidazol-2-yl) hydrazinocarbonylmethyl] -2,5-dioxoimidazolidin-1-yl) acetylamino] tert-butylpropionate (7.7) DCCI 44.7 mg at 0 ° C in DMF 5 ml. Inside (7.
6) 100 mg (0.2 mmol) and HOOBt 3
Add to a solution of 3.1 mg (0.2 mmol). After 1 hour at 0 ° C. and 1 hour at room temperature, 36.8 mg (0.2 mmol) of 2-hydrazino-2-imidazole hydrobromide are added and the mixture is stirred at room temperature for 3 days. The solvent is removed in vacuo and the residue is chromatographed on silica gel using dichloromethane / methanol / acetic acid / water = 8/2 / 0.2 / 0.2. The product fraction was concentrated and lyophilized. (7.7) 60 mg (5
2%). 7h) (2S) -benzyloxycarbonylamino-
3- [2-((4S)-(N '-(4,5-dihydro-1H
-Imidazol-2-yl) hydrazinocarbonylmethyl] -2,5-dioxoimidazolidin-1-yl) acetylamino] propionic acid (7.8) (7.7) 55 mg (0.096 mmol) 90 Stir in 1 ml of% trifluoroacetic acid for 1 hour at room temperature. Trifluoroacetic acid was removed in vacuo and the crude product was washed with RP 18
After purification by preparative HPLC through and then lyophilizing the product fraction, (7.8) 10.6 mg
(21%) was obtained as a colorless solid. ES (+)-MS: 519 (M + H) ⁺

Example 8 (2S) -Benzyloxycarbonylamino-3- [2
-(2,5-dioxo- (4S)-(N '-(1,4,5,
6-Tetrahydro-pyrimidin-2-yl) hydrazinocarbonylmethyl) imidazolidin-1-yl) acetylamino] propionic acid (8.2) The synthesis was prepared by the following reaction sequence.

Embedded image 8a) (2S) -benzyloxycarbonylamino-
3- [2- (2,5-dioxo- (4S)-(N'-
(1,4,5,6-tetrahydropyrimidin-2-yl)
Hydrazinocarbonylmethyl) imidazolidin-1-yl) acetylamino] tert-butyl propionate (8.
1) 58 mg of DCCI (7.6) 1 in 5 ml of DMF at 0 ° C
30 mg (0.26 mmol) and HOOBt 43 mg
(0.26 mmol) and the mixture at 0 ° C.
Stirred for 1 hour and at room temperature for 1 hour, 0.034 ml of N-ethylmorpholine (NEM) and 2-hydrazino-1,2.
52 mg of 4,5,6-tetrahydropyrimidine hydrobromide
(0.26 mmol) is added. After stirring for 28 hours at room temperature, the solvent was removed in vacuo and the residue was dichloromethane / methanol / acetic acid / water = 8.5 / 1.5 / 0.
Chromatography on silica gel using 15 / 0.15. The product fraction is concentrated and lyophilized. (8.1) 80 mg (52%) was obtained. 8b) (2S) -benzyloxycarbonylamino-
3- [2- (2,5-dioxo- (4S)-(N'-
(1,4,5,6-tetrahydropyrimidin-2-yl)
(Hydrazinocarbonylmethyl) imidazolidin-1-yl) acetylamino] propionic acid (8.2) 80 mg (0.1) (8.2) in 4 ml 90% trifluoroacetic acid.
A solution of 136 mmol) is stirred at room temperature for 1 hour and concentrated in vacuo. Then the residue is water / butanol /
Sephadex L using acetic acid = 43 / 4.3 / 3.5
Chromatograph on H20. Preparative HPL that concentrates the product fractions and passes through RP 18.
Purify by C. After concentrating the product fractions and freeze-drying 41.9 mg (59%) of (8.2) was obtained as a colorless solid. ES (+)-MS: 533 (M + H) ⁺

Example 9 2-benzyloxycarbonylamino-3- [2-((4
S)-(2- (N '-(4,5-dihydro-1H-imidazol-2-yl) hydrazinocarbonyl) ethyl)-
2,5-Dioxoimidazolidin-1-yl) acetylamino] propionic acid (9.1)

Embedded image (9.1) was synthesized as described in Example 7, starting from L-glutamic acid. ES (+)-MS: 533 (M + H) ⁺

Example 10 3-[(2-((4S)-(8 (1H-benzimidazol-2-ylmethyl) carbamoyl) methyl) -2,5-
Dioxoimidazolidin-1-yl) acetylamino]
-(2S) -Benzyloxycarbonylaminopropionic acid (10.2) The synthesis was carried out according to the following reaction sequence.

Embedded image 10a) 3-[(2-((4S)-(8 (1H-benzimidazol-2-ylmethyl) carbamoyl) methyl) -2,5-dioxoimidazolidin-1-yl) acetylamino]-(2S) Tert-Butyl benzyloxycarbonylaminopropionate (10.1) 192 mg DCCI at 0 ° C. in 10 ml DMF (7.
6) 430 mg (0.87 mmol) and HOOBt 1
Added to a solution of 42.5 mg (0.87 mmol). After 1 hour at 0 ° C. and 1 hour at room temperature, 2- (aminomethyl)
231 mg (1.04 mmol) benzimidazole and 0.5 ml diisopropylethylamine (DIPEA)
Is added and the mixture is stirred at room temperature for a further 2 hours. After standing overnight, the solvent was removed in vacuo and the residue was dichloromethane / methanol / acetic acid / water = 9.5 / 0.5 /
Chromatograph on silica gel using 0.05 / 0.05. After concentrating the product fractions,
(10.1) 390 mg (72%) were obtained. 10b) 3-[(2-((4S)-(8- (1H-benzimidazol-2-ylmethyl) carbamoyl) methyl) -2,5-dioxoimidazolidin-1-yl) acetylamino]-(2S ) -Benzyloxycarbonylaminopropionic acid (10.2) (10.1) 360 mg (0.579 mmol), 95%
Dissolve in 10 ml trifluoroacetic acid. After 30 minutes at room temperature, the solvent is removed in vacuo and the residue is partitioned between ethyl acetate and water, the aqueous phase is extracted with ethyl acetate and freeze-dried. The residue is water / butanol / acetic acid = 43 /
Chromatography on Sephadex LH20 using 4.3 / 3.5. The product fraction is concentrated and lyophilized. (10.2) 135 mg (40
%) As a colorless solid. ES (+)-MS: 566 (M + H) ⁺

Example 11 (2S) -Benzyloxycarbonylamino-3- [2
-((4S)-(3- (3H-imidazo [4,5-b] pyridin-2-ylamino) propyl) -2,5-dioxoimidazolidin-1-yl) acetylamino] propionic acid (11. 7) The synthesis was carried out according to the following reaction sequence.

Embedded image 11a) Methyl 4- (3-aminopropyl) -2,5-dioxoimidazolidin-1-yl] acetate hydrochloride (11.1) 12.5 ml (107 mmol) thionyl chloride and (1.
4) 21.5 g (85.4 mmol) are added at -15 DEG C. to 100 ml of methanol and the reaction mixture is stirred at room temperature for 24 hours. Then the solution is poured into diethyl ether and the precipitate is filtered off with suction and washed with diethyl ether. After drying under high vacuum, (11.1) 20.5
2 g (90%) was obtained as a colorless solid. 11b) [4- (3-isothiocyanatopropyl)
Methyl 2,5-dioxoimidazolidin-1-yl] acetate (11.2) 100 ml of a saturated solution of sodium hydrogen carbonate are suspended in a suspension of 2.65 g (10 mmol) of (11.1) in 30 ml of dichloromethane. Add. After stirring for 10 minutes while cooling with ice,
1.53 ml (20 mmol) of thiophosgene are added to the methylene chloride phase. The mixture is stirred for 10 minutes with ice cooling, the phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried over sodium sulphate. After filtering and removing the solvent in vacuo (11.2) 2.0
4 g (75%) was obtained.

11c) [(4S)-(3- (3- (3-aminopyridin-2-yl) thioureido) propyl)-
Methyl 2,5-dioxoimidazolidin-1-yl] acetate (11.3) (11.2) 1.66 g in 18 ml anhydrous ethanol
(6.11 mmol) and 2,3-diaminopyridine 6
A solution of 67 mg (6.11 mmol) is stirred at room temperature for 16 hours and then under reflux for 2 hours. The solvent is removed in vacuo and the residue is chromatographed on silica gel using dichloromethane / methanol / acetic acid / water = 9/1 / 0.1 / 0.1. After concentrating the product fractions and freeze-drying, (11.3) 1.67 g
(72%). 11d) [(4S)-(3- (3H-imidazo [4,5]]
Methyl pyridin-2-ylamino) propyl) -2,5-dioxoimidazolidin-1-yl] acetate (11.4) 1.62 g (7.51 mmol) mercuric oxide and 24 mg sulfuric acid in 80 ml ethanol. (11.3) 1.43g
(3.75 mmol) and the mixture is heated under reflux for 1 hour. After filtration and vacuum concentration of the filtrate,
(11.4) 1.15 g (89%) was obtained.

11e) [(4S)-(3- (3H-imidazo [4,5-b] pyridin-2-ylamino) propyl) -2,5-dioxo-imidazolidin-1-yl]
Acetate hydrochloride (11.5) (11.4) 286 mg (0.83 mmol) was added to concentrated HCl.
Stir in 10 ml at 50 ° C. for 5 hours. After filtration, the filtrate is diluted with water and freeze dried. (11.5) 277 mg
(91%) was obtained as a colorless solid. 11f) (2S) -benzyloxycarbonylamino-3- [2-((4S)-(3- (3H-imidazo- [4,
5-b] -pyridin-2-ylamino) propyl)-
2,5-Dioxoimidazolidin-1-yl] acetylamino] tert-butyl (11.6) O- [cyano (ethoxycarbonyl) methyleneamino] propionate
-1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU) 237 mg (0.72 mmol)
And diisopropylethylamine (DIPEA).
245 ml of 267 mg of (11.5) in 10 ml of DMF
(0.72 mmol) and (1.6) 213 mg (0.7)
2 mmol) and the mixture is stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate, then the ethyl acetate phase was washed with NaHCO 3.
Extract twice with a saturated solution of ₃ and twice with water. The organic phase is dried over sodium sulphate. After filtering and concentrating the filtrate in vacuo, 425 mg (97%) of (11.6) was obtained. 11 g) (2S) -benzyloxycarbonylamino-3- [2-((4S)-(3- (3H-imidazo [4,5
-B] pyridin-2-ylamino) propyl) -2,5
420 mg (0.69 mmol) of -dioxoimidazolidin-1-yl] acetylamino] propionic acid (11.7) (11.6) are dissolved in 10 ml of 95% trifluoroacetic acid. After 15 minutes at room temperature, the solution is concentrated in vacuo and the residue is taken up in water / butanol /
Acetic acid = 43 / 4.3 / 3.5 using Sephadex L
Chromatograph on H20. The product fraction is concentrated and lyophilized. (11.7) 2
Obtained 34 mg (62%) as a colorless solid. ES (+)-MS: 553 (M + H) ⁺

Example 12 (2S) -Benzyloxycarbonylamino-3- [2
-(4S)-(3- (3H-imidazo [4,5-c] pyridin-2-ylamino) propyl) -2,5-dioxoimidazolidin-1-yl) acetylamino] propionic acid (12.3 ) The synthesis was carried out by the following reaction sequence.

Embedded image The starting point for the synthesis of (12.3) is (11.2).
This compound was used in the same manner as in the production of (11.3) to give 3,4-
React with diaminopyridine to form (12.1). The latter compound was cyclized with mercuric oxide and concentrated in the same manner as in the preparations of (11.4) and (11.5).
React with l to form (12.2). (12.2)
As described for the preparation of (11.6) ((1.
6) and reacting the resulting coupling product with
While cleaving the tert-butyl ester as described for the synthesis of (11.7) from (11.6), (12.
Convert to 3). ES (+)-MS: 553 (M + H) ⁺

Example 13 (2S)-(adamanto-1-ylmethoxycarbonylamino) -3-[((4S)-(3- (benzimidazolyl-2-amino) propyl) -5-oxo-2-thio) Oxoimidazolidin-1-yl) acetylamino] propionic acid (13.7) The synthesis was carried out by the following reaction sequence.

Embedded image 13a) 5-benzyloxycarbonylamino- (2
Methyl S) -methoxycarbonylmethylamino-thiocarbonylamino-5-pentanoate (13.1) 2.62 g (20 mmol) methyl isothiocyanate acetate and 2.3 g N-ethylmorpholine (NEM).
(20 mmol) at 0 ° C in H-Or in 40 ml of DMF.
n (Z) -OMe.times.HCl (Bachem) 6.32 g (20 mmol) is added to the solution. After stirring for 20 hours at room temperature,
The solvent is removed in vacuo and the residue is taken up in dichloromethane, then the dichloromethane solution is extracted twice with water. The organic phase is dried over sodium sulphate, filtered and the solvent is removed in vacuo to give (13.1) and used directly in the synthesis of (13.2). 13b) [((4S)-(3-aminopropyl)]-5
50% of a suspension of (13.1) in 150 ml of -oxo-2-thioxoimidazolidin-1-yl) acetic acid hydrochloride (13.2) 6N HCl.
Stir at C for 5 hours. The solution is concentrated and the residue is thoroughly stirred twice with diethyl ether. After drying the residue under high vacuum and then on KOH,
(13.2) is obtained and used directly in the synthesis of (13.3).

13c) 2-[(4S)-(3- (3-
(2-Nitrophenyl) thioureido) propyl) -5-
Oxo-2-thioxo-imidazolidin-1-yl] acetic acid (13.3) Triethylamine 2.77 ml (20 mmol) was cooled with ice while (13.2) and 2-nitrophenyl isothiocyanate in 50 ml DMF. Add dropwise to a solution of 3.6 g (20 mmol). The solution was stirred overnight at room temperature and then further 2-nitrophenyl isothiocyanate 36.
0 mg (2 mmol) and 0.8 ml triethylamine are added and the mixture is stirred at room temperature for a further 5 hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate,
The ethyl acetate phase is then washed twice with an aqueous solution of KHSO ₄ / K ₂ SO ₄ and dried over sodium sulphate. After filtration, ethyl acetate was removed in vacuo and the residue was converted to dichloromethane / methanol / acetic acid / water = 9/1 / 0.1
Chromatography on silica gel using /0.1. After concentrating the product fractions (13.
3) 4.06 g [49% based on (13.1)] was obtained. 13d) 2-[(4S)-(3- (3- (2-aminophenyl) thioureido) propyl) -5-oxo-2-
Thioxo-imidazolidin-1-yl] acetic acid (13.
4) (13.
3) 611 mg (1.48 mmol) of 10% Pd / C60
Hydrogenate over 0 mg at room temperature for 3 hours. After filtering and concentrating the filtrate in vacuo, (13.4) 488 mg (87
%) Was obtained.

13e) [(4S)-(3- (benzimidazolyl-2-amino) propyl) -5-oxo-2
-Thioxoimidazolidin-1-yl] acetic acid (13.
5) 550 mg (2.54 mmol) of mercuric oxide and 8.1 mg of sulfur were added to 485 mg of (13.4) in 50 ml of ethanol.
(1.27 mmol) and the mixture is heated under reflux for 3 hours. After filtering and removing the solvent in vacuo, the residue is taken up in 10% acetic acid and the solution is freeze-dried. 307 mg (79%) of (13.5) was obtained as a colorless solid. 13f) (2S)-(adamanto-1-ylmethoxycarbonylamino) -3-[((4S)-(3- (benzimidazolyl-2-amino) propyl) -5-oxo-
Tert-Butyl 2-thioxoimidazolidin-1-yl) acetylamino] propionate (13.6) 273 mg (0.834 mmol) TOTU in anhydrous DMF and diisopropylethylamine (DIPEA).
0.28 ml was replaced with 290 mg (0.834 mmol) of (13.5) and (13.11) (synthesis, see 13h-k) 2
Add to a solution of 97 mg (0.834 mmol). The mixture is stirred at room temperature for 2.5 hours. The solvent is removed in vacuo and the residue is taken up in ethyl acetate, then the ethyl acetate phase is extracted twice with a saturated solution of sodium hydrogen carbonate and water. After drying over sodium sulphate, the ethyl acetate was removed in vacuo and the residue was washed on silica gel using dichloromethane / methanol / acetic acid / water = 9.5 / 0.5 / 0.05 / 0.05. Chromatography. After concentrating the product fraction, (13.6) 46.3 mg
(8%) was obtained. 13 g) (2S)-(adamanto-1-ylmethoxycarbonylamino) -3-[((4S)-(3- (benzimidazolyl-2-amino) propyl) -5-oxo-
2-Thioxoimidazolidin-1-yl) acetylamino] propionic acid (13.7) (13.6) 38.1 mg (0.056 mmol)
Dissolve in 2 ml of% trifluoroacetic acid. After 10 minutes at room temperature, the solution was concentrated in vacuo and the residue was purified by preparative HP.
Purify by LC (RP 18). After freeze-drying the product fraction, (13.7) 11 mg (32%)
I got FAB-MS: 626 (M + H) ⁺

3-amino- (2S)-(adamant-1
Synthesis of tert-Butyl 3-ylmethoxycarbonylamino) propionate (13.11) The synthesis was carried out according to the following reaction sequence.

Embedded image 13h) (2S) -benzyloxycarbonylamino-3-tertiary butoxycarbonylaminopropionic acid tertiary
Butyl (13.8) di-tert-butyl dicarbonate 8.9 g (40.8 mmol) at 0 ° C. tetrahydrofuran / water = 2/16
To a solution of 10 g (34 mmol) of (1.6) in 00 ml, then add 1 N NaOH in small portions so as to keep the pH of the solution between 9 and 10 (consumption of 1 N NaOH: 32 ml). . After stirring for 3 hours at room temperature, 1 liter of water is added and the mixture is extracted 3 times with diethyl ether. After drying over sodium sulphate, filtering and removing the solvent in vacuo, the residue is chromatographed on silica gel using dichloromethane / methanol = 20/1. There was obtained 13.19 g (98%) of (13.8). 13i) (2S) -Amino-3-tert-butoxycarbonylaminopropionic acid tert-butyl hydrochloride (13.9) (13.8) 13.1 g (33.2 mmol) in methanol / HCl 10%. Hydrogenate over Pd / C. 1.5
After time, the mixture is filtered and the filtrate is concentrated in vacuo. Obtained 9.77 g (99%) of (13.9) as a colorless solid.

13j) (2S)-(Adamant-1-
Ilemethoxycarbonylamino) -3-tert-butylbutoxycarbonylaminotert-butylpropionate (13.10) 10.9 g (65.4 mmol) (1-hydroxymethyl) adamantane and 10.6 g carbonyldiimidazole in 60 ml THF. A solution of (65.4 mmol)
Stir at 50 ° C. for 1.5 hours. 25 ml of THF and 5.6 ml of diisopropylethylamine (DIPEA) (32.
9.7 g (32.7 mmol) of (13.9) in 7 mmol) are added and the mixture is stirred at 60 ° C. for 4 hours and then left at room temperature overnight. The solvent is removed in vacuo and the residue is chromatographed on silica gel with heptane / ethyl acetate = 7/3. (13.
10) Obtained 8.7 g (59%) as a colorless oil. 13k) (2S)-(adamanto-1-ylmethoxycarbonylamino) -3-aminopropionate tert-butyl (13.11) trifluoroacetic acid / dichloromethane = 1/1 180 ml
A solution of 8.7 g (19.22 mmol) of (13.10) in 1 is added after 1 minute to 1.5 ml of an ice-cold solution of NaHCO ₃ .
This solution is extracted 3 times with dichloromethane and then the dichloromethane phase is dried over sodium sulphate. After filtering and removing the solvent in vacuo (13.11)
Obtained 635 g (94%) as a colorless solid.

Example 14 3- [2-((4R, S)-(3- (1H-benzimidazol-2-ylamino) propyl) -4-methyl-2,5-
Dioxo-imidazolidin-1-yl) acetylamino]-(2S) -benzyloxycarbonylaminopropionic acid (14.8) The synthesis was carried out by the following reaction sequence.

[0126]

Embedded image

14a) 2- (4-Oxopentyl) isoindole-1,3-dione (14.1) 24.59 g (132.8 mmol) potassium phthalimide are treated with 5-chloro-2-pentanone in 100 ml DMF. It is added to a solution of 14.3 ml (124.4 mmol) and the mixture is stirred at room temperature for 3 hours and at 60 ° C. for 30 hours. After filtration, the filtrate is partitioned between water and dichloromethane. The phases are separated and the organic phase is successively washed with water, NaO.
Wash twice with a 0.2N solution of H and with water and then dry over sodium sulfate. After filtration, the solvent was removed in vacuo and the residue was heptane / ethyl acetate = 6
Chromatography on silica gel using / 4. After concentrating the product fraction, (14.1)
9.8 g (34%) were obtained.

14b) 13 g (56.2 mmol) of 5-amino-2-oxopentane hydrochloride (14.2) (14.1) are dissolved in 335 ml of 20% hydrochloric acid and the solution is heated to reflux for 6 hours. .
After standing overnight at room temperature, the mixture is filtered and the filtrate is
Concentrate in vacuo. A pale yellow oil of crude product (14.2) was obtained. This oil was used directly for the synthesis of (14.3).

14c) 5-tert-Butoxycarbonylamino-2-oxopentane (14.3) (14.2) (from 14b) is dissolved in 110 ml dioxane and 55 ml water and the solution is treated with 1N NaOH 6
The pH is adjusted to 8.5 by adding 5 ml. 13.25 g (60.8 mmol) of di-tert-butyl dicarbonate was added at 0 ° C.
And the pH of the solution is adjusted to 8.5 by repeated addition of 1N NaOH. After stirring for 4.5 hours at room temperature,
Dioxane was removed in vacuo and the pH of the residual solution was adjusted to K
Adjust to 2-3 by addition of HSO ₄ / K ₂ SO ₄ solution, then extract the solution with ethyl acetate three times. The combined organic phases are washed with a saturated solution of sodium hydrogen carbonate and then dried over sodium sulphate. After filtering and removing the solvent in vacuo, (14.3) 11.1 g
[Starting from (14.1) 99%] was obtained.

14d) (4R, S)-(3-tert-Butoxycarbonylamino) propyl-4-methyl-2,5-dioxo-imidazolidine (14.4) 41.96 g (439.2 mmol) ammonium carbonate. And 4.2 g (65.1 mmol) of potassium cyanide,
Ethanol / water = 1/1 (14.3) 1 in 130 ml
Add to a solution of 0.06 g (50 mmol) and heat the mixture to 55-65 ° C. After 5.5 hours at this temperature, the pH of the reaction mixture was adjusted to 6.3 with 100 ml of 6N HCl.
And then the mixture is stirred for a further 2 hours. Then the mixture is left at room temperature overnight, after which the solvent is removed in vacuo and the residue is partitioned between water and ethyl acetate. The phases are separated and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulphate,
Then the desiccant is filtered off and the solvent is eliminated i. 12.42 g (92%) of (14.4) were obtained as colorless crystals.

14e) [(4R, S)-(3-tert-butoxycarbonylaminopropyl) -4-methyl-2,5-
Dioxo-imidazolidin-1-yl] ethyl acetate (1
4.5) 388 mg (16.1 mmol) sodium hydride under ice cooling and under an atmosphere of argon D
A solution of 4 g (14.7 mmol) of (14.4) in 100 ml of MF is added and the mixture is stirred for 45 minutes at room temperature. 1.63 ml (14.7 mmol) of ethyl bromoacetate are added and the mixture is stirred at room temperature for 3 hours, then the solvent is removed in vacuo. The residue is dissolved in ethyl acetate and the ethyl acetate phase is washed twice with water. After drying over sodium sulfate and removing the solvent in vacuo, (1
4.5) 4.98 g (85%) were obtained as a pale yellow oil.

14f) [(4R, S)-(3-Aminopropyl) -4-methyl-2,5-dioxoimidazolidin-1-yl] acetic acid hydrochloride (14.6) (14.5) 4 .98 g (13.9 mmol) of 6N H
Suspended in 50 ml Cl and heated the suspension to reflux for 1 hour. The reaction mixture is concentrated in vacuo and the residue is dissolved in water and freeze dried. (14.6) was obtained as a crude product and used directly in the synthesis of (14.7).

The synthesis of (14.7) starting from (14.6) and the synthesis of (14.8) starting from (14.7) of (5.5) starting from (1.4). Synthesis (Example 5)
See). (14.8): ES (+)-MS: 566 (M + H) ⁺

Example 15 (2S) -Benzyloxycarbonylamino-3-[((4
S)-(3- (6-Methoxy-1H-benzimidazol-2-ylamino) propyl) -2,5-dioxoimidazolidin-1-yl) acetylamino] propionic acid (15.3) The reaction sequence was as follows.

[0135]

Embedded image

The starting point for synthesizing (15.3) is (11.2)
It is. This compound is reacted with 4-methoxyorthophenylenediamine at room temperature in analogy to the preparation of (11.3) to form (15.1). The latter compound is then cyclized with mercuric oxide and reacted with concentrated HCl to form (15.2), analogously to the preparation of (11.4) and (11.5). Then (15.2)
As described for the production of (11.6),
Reaction with (1.6) and the resulting coupling product was carried out as described for the synthesis of (11.7) from (11.6) with cleavage of the tert-butyl ester (1
Convert to 5.3). ES (+)-MS: 582 (M + H) ⁺

Example 16 (2S) -benzyloxycarbonylamino-3-[((4
S)-(3- (5,6-Dimethoxy-1H-benzimidazol-2-ylamino) propyl) -2,5-dioxoimidazolidin-1-yl) acetylamino] propionic acid (16.1)

[0138]

Embedded image

(16.1) describes 1,2-dimethoxy-4,5-diaminobenzene by hydrogenation over 10% Pd / C in methanol instead of using 1-methoxy-3,4-diaminobenzene. 1,2 produced from nitrobenzene
-Synthesized as described for the preparation of (15.3) by using dimethoxy-4,5-diaminobenzene.

Example 17 (2S) -Benzyloxycarbonylamino-3-[((4
S)-(3- (5,6-Methylenedioxy-benzimidazol-2-ylamino) propyl) -2,5-dioxoimidazolidin-1-yl) acetylamino] propionic acid (17.1)

[0141]

Embedded image

(17.1) gives 1,2-methylenedioxy-4, by hydrogenation over 10% Pd / C in methanol instead of using 1-methoxy-3,4-diaminobenzene. Synthesized as described for the preparation of (15.3) by using 1,2-methylenedioxy-4,5-diaminobenzene prepared from 5-dinitrobenzene.

Example 18 3- [2-((4S)-(2- (1H-benzimidazol-2-yl) ethyl) -2,5-dioxo-imidazolidin-1-yl) acetylamino]-( 2S) -Benzyloxycarbonylaminopropionic acid (18.5) The synthesis was carried out by the following reaction sequence.

[0144]

Embedded image

18a) Methyl (2S) -amino-4- (2-benzimidazolyl) butanoate (18.1) (18.1) was prepared according to Hans Lettre et al., Berichte 1951, 8
Prepared as described in 4,719.

18b) (2S) -Ethyloxycarbonylmethylaminocarbonylamino-4- (2- (1H-
Methyl benzimidazolyl) butanoate (18.2) Diisopropylethylamine (DIP in anhydrous DMF
EA) (3.4 ml, 20 mmol) and ethyl isocyanate ethyl acetate (2.58 g, 20 mmol) were added at 0 ° C. to (1
8.1) Add to a solution of 4.6 g (20 mmol). After stirring for 16 hours at room temperature, the solvent is removed in vacuo and the residue is taken up in ethyl acetate, then the ethyl acetate phase is washed twice with a 10% solution of citric acid. 2N K aqueous phase
The pH is adjusted to 10 with OH solution and extracted several times with ethyl acetate. The combined organic phases are dried over sodium sulphate, the desiccant is filtered off and the filtrate is concentrated in vacuo. (18.
2) 4.4 g (61%) was obtained.

18c) [(4S)-(2- (1H-Benzimidazol-2-yl) ethyl) -2,5-dioxoimidazolidin-1-yl] acetic acid (18.3) 4N HCl in 4 ml. A solution of 200 mg (0.55 mmol) of (18.2) is stirred at room temperature for 16 hours. After removing the solvent in vacuo, the residue is taken up in water and the solution is freeze-dried. 160 mg (53%) of (18.3) was obtained as a colorless solid.

18d) 3- [2-((4S)-(2- (1
H-benzimidazol-2-yl) ethyl) -2,5
-Dioxo-imidazolidin-1-yl) acetylamino]-(2S) -benzyloxycarbonylaminopropionate tert-butyl (18.4) diisopropylethylamine (DIPEA) 0.09 ml
(0.53 mmol) and DCCI 120 mg (0.5
8 mmol) at 0 ° C. in 5 ml of DMF (18.3)
160 mg (0.53 mmol), HOBt 72 mg (0.5
53 mmol) and (1.6) to a solution of 156 mg (0.53 mmol). The mixture is stirred at 0 ° C. for 20 minutes and at room temperature for 16 hours. The precipitate is filtered off, the filtrate is concentrated and the residue is taken up in ethyl acetate, then the ethyl acetate phase is washed with a 10% solution of KHCO ₃ and a saturated solution of NaCl and dried over sodium sulphate. After filtration,
The solvent is removed in vacuo and the residue (18.4) is converted directly (18.5).

18e) 3- [2-((4S)-(2- (1H
-Benzimidazol-2-yl) ethyl) -2,5-dioxoimidazolidin-1-yl) acetylamino]-
(2S) -Benzyloxycarbonylaminopropionic acid (18.5) A solution of ((18.4) crude product) in 5 ml of 95% trifluoroacetic acid is stirred for 20 minutes at room temperature. The solvent is removed in vacuo and the residue is dissolved in tert-butanol / water = 1/1 and the solution is freeze-dried. (18.5) 12
Obtained 0 mg (44% starting from (18.3)) as a pale yellow solid. ES (+)-MS: 492 (M + H) ⁺

Example 19 (2S) -Benzyloxycarbonylamino-3- [2-
((4S)-(3-guanidino-3-oxopropyl) -2,
5-Dioxoimidazolidin-1-yl) acetylamino] propionic acid (19.3) The synthesis was carried out by the following reaction sequence.

[0151]

Embedded image

19a) (2S) -Benzyloxycarbonylamino-3-[((4S)-(2-carbonylethyl))
Tert-Butyl-2,5-dioxoimidazolidin-1-yl) acetylamino] propionate (19.1) (19.1) is the synthesis of (7.6) from L-aspartic acid (Example) 7)) and is synthesized starting from L-glutamic acid.

19b) (2S) -Benzyloxycarbonylamino-3- [2-((4S)-(3-guanidino-3)
-Oxopropyl) -2,5-dioxoimidazolidine-
1-yl) Acetylamino] tert-butyl propionate (19.2) 12.8 mg (0.09 mmol) lithium iodide and DM
A solution of 500 mg (0.91 mmol) of (19.1) in 5 ml of F was added to 170 mg (2.88 mg) of guanidine in 2 ml of DMF.
Mmol) and 6.5 mg (0.09 mmol) of imidazole and the mixture is stirred at room temperature overnight.
The solvent is removed in vacuo and the residue is treated with ethyl acetate, then the ethyl acetate phase is washed with KHCO ₃ solution and dried over sodium sulphate. After filtration, the solvent was removed in vacuo and 30 mg (19.2, crude product) were obtained and used directly in the synthesis of (19.3).

19c) (2S) -Benzyloxycarbonylamino-3- [2-((4S)-(3-guanidino-3)
-Oxopropyl) -2,5-dioxoimidazolidine-
1-yl) -acetylamino] propionic acid (19.
3) A solution of 30 mg (19.2, crude product) in 1 ml 95% trifluoroacetic acid is stirred for 10 minutes at room temperature. The solvent is removed in vacuo and the residue is purified by preparative HPLC through RP 18. After concentrating the product fractions and freeze-drying, (19.3) 9.5 mg [(1
2%] starting from 9.1). ES (+)-MS: 492 (M + H) ⁺

Example 20 (2S) -Benzyloxycarbonylamino-3- [2-
(2,5-Dioxo- (4S)-(2- (1,4,5,6-tetrahydro-pyrimidin-2-ylcarbamoyl) ethyl) imidazolidin-1-yl) acetylamino] propionic acid (20.2 ) The synthesis was performed according to the following reaction sequence.

[0156]

Embedded image

20a) (2S) -Benzyloxycarbonylamino-3- [2- (2,5-dioxo- (4S)-
(2- (1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl) ethyl) imidazolidin-1-yl)
Acetylamino] tert-butyl propionate (20.1) HOBt 135 mg (1 mmol) and DCCI 20
6 mg (1.1 mmol) are added to a solution of 506 mg (1 mmol) (19.1) in 4 ml anhydrous tetrahydrofuran with ice cooling and the mixture is stirred for 30 minutes. This solution was then added to 136 mg (1 of 1,4,5,6-tetrahydropyrimidin-2-ylamine hydrochloride in DMF).
Mmol) and 112 mg of potassium tert-butoxide and the mixture is stirred at room temperature for 1 hour. The solvent is removed in vacuo and the residue is triturated with diethyl ether. After chromatography on silica gel using dichloromethane / methanol / acetic acid / water = 9/1 / 0.1 / 0.1 and concentrating the product fractions and freeze-drying, (20.1) 90 mg ( 15%).

20b) (2S) -Benzyloxycarbonylamino-3- [2- (2,5-dioxo-4- (2-
(1,4,5,6-Tetrahydro-pyrimidin-2-ylcarbamoyl) ethyl) -imidazolidin-1-yl) acetylamino] propionic acid (20.2) (20.1 in 95% trifluoroacetic acid 10 ml). ) 80 mg
A solution of (0.136 mmol) is stirred at room temperature for 20 minutes. The solvent is removed in vacuo and the residue is dissolved in water and the solution is freeze dried. (20.2) 70 mg (9
7%) was obtained as a colorless solid. ES (+)-MS: 532 (M + H) ⁺

Example 21 4-[(4R, S)-(4-((1H-benzimidazole-
2-ylamino) methyl) phenyl) -4-methyl-2,5
-Dioxoimidazolidin-1-yl] -2-benzyloxycarbonylaminobutanoic acid (21.7) The synthesis was carried out by the following reaction sequence.

[0160]

Embedded image

21a) 2-Benzyloxycarbonylamino-4-[(4R, S)-(4-cyanophenyl) -4
-Methyl-2,5-dioxoimidazolidin-1-yl] butanoic acid (21.2) A solution of 870 mg (0.5 mmol) diethyl azodicarboxylate (DEAD) in anhydrous tetrahydrofuran was added to
1.07 g (5 mmol) of (21.1) (see synthesis WO 95/14008), 1.3 g (5 mmol) of triphenylphosphine in 20 ml of anhydrous tetrahydrofuran.
And (21.10) to a solution of 1.7 g (5 mmol). After stirring for 16 hours at room temperature, the solvent is removed in vacuo and the residue is taken up in ethyl acetate, then the ethyl acetate phase is washed with a 10% solution of citric acid and a saturated solution of NaHCO ₃ and dried over sodium sulfate. To do.
After filtration, the solvent is removed in vacuo and the residue is chromatographed on silica gel with dichloromethane / tert-butyl methyl ether = 1/1. After concentrating the product fraction, (21.2) 1.2 g (44
%) Was obtained.

21b) 4-[(4R, S)-(4-Aminomethylphenyl) -4-methyl-2,5-dioxoimidazolidin-1-yl] -2-benzyloxycarbonylaminobutanoic acid benzylacetic acid Salt (21.3) A solution of 1.2 g (2.22 mmol) of (21.2) in acetic acid is hydrogenated over 150 mg of platinum oxide. As soon as the uptake of hydrogen (about 3 hours), the catalyst is filtered off, the filtrate is concentrated and the residue is taken up in dichloromethane / methanol /
Purify through silica gel using acetic acid / water = 6/1 / 0.1 / 0.1. After concentration of the product fraction, (2
1.3) 450 mg (34%) were obtained.

21c) 2-Benzyloxycarbonylamino-4-[(4R, S) -methyl-4- (4- (3- (2
-Nitrophenyl) thioureidomethyl) phenyl)-
Benzyl 2,5-dioxoimidazolidin-1-yl] butanoate (21.4) 135 mg of 2-nitrophenyl isothiocyanate (0.7
5 mmol) and diisopropylethylamine (DI
PEA) 0.13 ml to (21.3) 4 in 5 ml DMF
Add to a solution of 10 mg (0.75 mmol). 1 at room temperature
After stirring for 6 hours, the solvent is removed in vacuo and the residue is chromatographed on silica gel using tert-butyl methyl ether. (21.4) 380mg
(70%).

21d) 4-[(4R, S)-(4- (3-
(2-Aminophenyl) thioureamethyl) phenyl)-
Benzyl 4-methyl-2,5-dioxoimidazolidin-1-yl] -2-benzyloxycarbonylaminobutanoate (21.5) 650 mg (2.9 mmol) SnCl ₂ × 2H ₂ O and 3 drops acetic acid were added. , 360 mg of (21.4) in 5 ml of methanol
(0.49 mmol) is added to the solution and the mixture is stirred at room temperature for 16 hours. After removing the solvent in vacuo, the residue is chromatographed on silica gel using dichloromethane / methanol = 20/1. (2
1.5) 280 mg (82%) was obtained.

21e) 4-[(4R, S)-(4-((1H
-Benzimidazol-2-ylamino) methyl) phenyl) -4-methyl-2,5-dioxoimidazolidin-1-yl] -2-benzyloxycarbonylaminobutanoic acid benzyl (21.6) (21.5) A mixture of 270 mg (0.38 mmol), 173 mg mercuric oxide (0.8 mmol) and 3 mg sulfur is heated to reflux in 10 ml ethanol for 12 hours. After filtering and removing the solvent in vacuo, 180 mg (21.6, crude product) were obtained as a red-brown syrup. This was directly converted to (21.7).

21f) 4-[(4R, S)-(4-((1H
-Benzimidazol-2-ylamino) methyl) phenyl) -4-methyl-2,5-dioxoimidazolidine-
1-yl] -2-benzyloxycarbonylaminobutanoic acid (21.7) 0.27 ml of a 1M solution of LiOH in 4 ml of dioxane.
(21.6, crude product) 180 mg (about 0.27 mmol)
Solution and the mixture is stirred overnight at room temperature. Most of the dioxane is removed in vacuo, the aqueous residue is adjusted to pH 5 with citric acid and the aqueous phase is extracted with ethyl acetate. After drying over sodium sulfate, filtering and concentrating the filtrate in vacuo, the residue is chromatographed on silica gel using dichloromethane / methanol / acetic acid / water = 6/1 / 0.1 / 0.1. Graphography. After concentrating the product fractions and freeze-drying (21.7)
107 mg [49% starting from (21.5)] were obtained as a colorless solid. ES (+)-MS: 571 (M + H) ⁺

21 g) Benzyl 2-benzyloxycarbonylamino-4-hydroxybutanoate (21.1
Synthesis of 0) The synthesis was carried out by the following reaction sequence.

[0168]

Embedded image

420m 0.1M NaOH in ethanol
A suspension of 10 g (42 mmol) of (21.8) in 1
Stir at room temperature for 16 hours. The reaction solution is concentrated, the residue treated with toluene and the solvent removed in vacuo. DM
130 ml F and benzyl bromide 9.34 g (54.6 mmol) are added and the mixture is stirred at room temperature for 4 days. 2.1 liters of 1M NaHCO ₃ solution are added and the whole is extracted 3 times with ethyl acetate. The combined ethyl acetate phases are washed with 1M NaHCO ₃ solution and saturated solution of NaCl and dried over magnesium sulphate. After filtration,
The solvent is removed in vacuo and the residue is chromatographed on silica gel using dichloromethane / acetonitrile = 20 / 1-20 / 6. The product fractions are concentrated and the residue is crystallized using diethyl ether / hexane. (21.10) 5.4g
(38%) was obtained as colorless crystals.

Example 22 3- [2-((4S)-(3- (1H-benzimidazol-2-ylamino) propyl) -2,5-dioxoimidazolidin-1-yl) acetylamine]-( 2S)-(2
-Chlorobenzyloxycarbonylamino) propionic acid (22.4) The synthesis was carried out by the following reaction sequence.

[0171]

[Chemical formula 106]

22a) 3- [2-((4S)-(3- (1
- third butoxycarbonyl-benzimidazol-2-ylamino) propyl) -2,5-dioxo-imidazolidin-1-yl) acetylamino] - (2S) - benzyloxycarbonylamino acid (22.1) NaHCO ₃ 168 mg (2 mmol) and 437 mg (2 mmol) di-tert-butyl dicarbonate are added to a solution of 551 mg (1 mmol) (5.5) in 4 ml dioxane / water = 1/1 and the mixture is stirred for 16 hours at room temperature. To do. The solvent is removed in vacuo and the residue is taken up in ethyl acetate, then the ethyl acetate phase is washed with a 2% solution of citric acid and a saturated solution of NaCl and dried over magnesium sulphate. After filtration the solvent was removed in vacuo and 614 mg (94%) of (22.1) were obtained as colorless crystals.

22b) (2S) -amino-3- [2-
((4S)-(3- (1-tert-Butoxycarbonylbenzimidazol-2-ylamino) propyl) -2,5-dioxoimidazolidin-1-yl) acetylamino] propionic acid (22.2) in methanol A solution of (22.1) in 600 mg (0.92 mmol) of is hydrogenated over palladium hydroxide. The catalyst is filtered off, the filtrate is concentrated and the residue is subjected to rotary evaporation twice using toluene, then it is dried under high vacuum. 385 mg (81%) of (22.2) was obtained.

22c) 3- [2-((4S)-(3- (1
-Tert-butoxycarbonylbenzimidazol-2-ylamino) propyl) -2,5-dioxoimidazolidin-1-yl) acetylamino]-(2S)-(2-chlorobenzyloxycarbonylamino) propionic acid (2
2.3) Diisopropylethylamine 0.017 ml and then a solution of 28.4 mg (0.1 mmol) N- (2-chlorobenzyloxycarbonyloxy) succinimide at 0 DEG C. in 2.5 ml DMF (22. 2) 61.7mg
(0.12 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The solvent is removed in vacuo and the residue is partitioned between ethyl acetate and 2% citric acid. The phases are separated and the organic phase is dried over magnesium sulphate. After filtration, the filtrate was concentrated in vacuo and the residue was crystallized using diethyl ether, then (22.
3) 36.5 mg (45%) were obtained as colorless crystals.

22d) 3- [2-((4S)-(3- (1
H-benzimidazol-2-ylamino) propyl)
-2,5-Dioxo-imidazolidin-1-yl) acetylamino]-(2S)-(2-chlorobenzyloxycarbonylamino) -propionic acid (22.4) (22.4%) in 3 ml of 95% trifluoroacetic acid. 3) 36.5mg
The solution of is stirred at room temperature for 1 hour. Trifluoroacetic acid is removed in vacuo and the residue is subjected to rotary evaporation twice using toluene. The residue is dissolved in methanol and (22.4) is precipitated with diethyl ether.
After centrifugation, the residue is taken up in dilute acetic acid and the solution is freeze-dried. 24 mg (77%) of (22.4) was obtained as a colorless solid. ES (+)-MS: 586 (M + H) ⁺

Examples 23-33 Compounds (23)-(33) were prepared by the following reaction sequence.

[0177]

Embedded image

Example 23

Embedded image 3- [2-((4S)-(3- (1H-benzimidazol-2-ylamino) propyl) -2,5-dioxoimidazolidin-1-yl) -acetylamino]-(2S)-
(3,4-dimethoxybenzyloxycarbonylamino)
Propionic acid (23) ES (+)-MS: 612 (M + 1) ⁺

Example 24

Embedded image 3- [2-((4S)-(3- (1H-benzimidazol-2-ylamino) propyl) -2,5-dioxoimidazolidin-1-yl) -acetylamino]-(2S)-
(3,4-Methylenedioxybenzyloxycarbonylamino) propionic acid (24) ES (+)-MS: 624 (M + 1) ⁺

Example 25

Embedded image 3- [2-((4S)-(3- (1H-benzimidazol-2-ylamino) propyl) -2,5-dioxoimidazolidin-1-yl) acetylamino]-(2S)-(4
-Chlorobenzyloxycarbonylamino) propionic acid (25) ES (+)-MS: 586 (M + 1) ⁺

Example 26

[Chemical 111] 3- [2-((4S)-(3- (1H-benzimidazol-2-ylamino) propyl) -2,5-dioxoimidazolidin-1-yl) acetylamino]-(2S)-(4
-Tert-Butylbenzyloxycarbonylamino) propionic acid (26) ES (+)-MS: 608 (M + 1) ⁺

Example 27

[Chemical 112] 3- [2-((4S)-(3- (1H-benzimidazol-2-ylamino) propyl) -2,5-dioxoimidazolidin-1-yl) acetylamino]-(2S)-(3
-Chlorobenzyloxycarbonylamino) propionic acid (27) ES (+)-MS: 586 (M + 1) ⁺

Example 29

[Chemical 113] 3- [2-((4S) -3- (1H-benzimidazole-
2-ylamino) propyl) -2,5-dioxoimidazolidin-1-yl) acetylamino]-(2S)-(4-
Trifluoromethylbenzyloxycarbonylamino)
Propionic acid (29) ES (+)-MS: 620 (M + 1) ⁺

Example 30

Embedded image 3- [2-((4S)-(3- (1H-benzimidazol-2-ylamino) propyl) -2,5-dioxoimidazolidin-1-yl) acetylamino]-(2S)-(4
-Phenylbenzyloxycarbonylamino) propionic acid (30) ES (+)-MS: 628 (M + 1) ⁺

Example 31

[Chemical 115] 3- [2-((4S)-(3- (1H-Benzimidazol-2-ylamino) propyl) -2,5-dioxoimidazolidin-1-yl) acetylamino]-(2S)-(naphtho- 1-ylmethoxycarbonylamino) propionic acid (31) ES (+)-MS: 602 (M + 1) ⁺

Example 32

Embedded image 3- [2- (4S)-(3- (1H-Benzimidazol-2-ylamino) propyl) -2,5-dioxoimidazolidin-1-yl) acetylamino]-(2S)-(naphth-2 -Ylmethoxycarbonylamino) propionic acid (32) ES (+)-MS: 602 (M + 1) ⁺

Example 33

[Chemical 117] (2S)-(Benzofuran-3-ylmethoxycarbonylamino) -3- [2-((4S)-(3- (1H-benzimidazol-2-ylamino) propyl) -2,5-dioxoimidazolidine- 1-yl) acetylamino] propionic acid (33) ES (+)-MS: 592 (M + 1) ⁺

A) Chloroformate (23.2)-
Preparation of (33.2) The synthesis is carried out according to the following general manufacturing protocol. The corresponding alcohol (H
A solution of 6 equivalents of OR and 6 equivalents of pyridine was added at 0 ° C.
, Dropwise to a solution of 2.2 equivalents of bis (trichloromethyl) carbonate in anhydrous dichloromethane. The mixture is then stirred at room temperature for 2 hours, after which the solvent is removed in vacuo and the residue is taken up in ethyl acetate or ether. The mixture is left at room temperature for 30 minutes and then the precipitate obtained is filtered off. After removing the solvent in vacuo, the residue is dried under high vacuum and (23.
Used directly in the synthesis of 1)-(33.1).

B) Preparation of compounds (23.1) to (33.1) The synthesis is carried out according to the following general manufacturing protocol. Corresponding chloroformates (23.2) to (33.
2) 1 equivalent and diisopropylethylamine (DIP
EA) 1 equivalent is added to a solution of 1 equivalent of N-hydroxysuccinimide in THF at 0 ° C. Mix at 0 ° C. for 3
Stir for 0 min and 45 min at room temperature and then add this solution to a solution of (22.2) 1 eq in DMF.
The mixture is stirred at room temperature until the reaction is complete and the solvent is removed in vacuo. The residue is taken up in ethyl acetate and the ethyl acetate phase is washed twice with an aqueous solution of citric acid (pH 3) and with a saturated solution of NaCl. After drying over sodium sulphate, filtering and removing the solvent in vacuo, the residue is chromatographed on silica gel.
After concentration of the product fraction, the compound (23.1) ~
(33.1) was obtained.

C) Preparation of compounds (23)-(33) The preparation was carried out as described for the preparation of (22.4) from (22.3) with 95% trifluoroacetic acid in the tert-butoxycarbonyl group. By cleaving (23.
It carried out from 1)-(33.1).

Example 34 3- [8- (3- (1H-benzimidazol-2-ylamino) propionyl) -2,4-dioxo-1,3,8-
Triaza-spiro [4.5] dec-3-yl]-(2S)
-Benzyloxycarbonylaminopropionic acid (3
4.12) The synthesis was carried out according to the following reaction sequence:

[0192]

Embedded image

34a) Tertiary butyl 2,4-dioxo-1,3,8-triazaspiro [4.5] decane-8-carboxylate (34.2) 2.12 g (32.6 mmol) potassium cyanide was added to E
To a solution of 5 g (25.1 mmol) of N-tert-butoxycarbonyl-4-piperidone (34.1) and 24.01 g (250 mmol) of ammonium carbonate in tOH / water = 1/180 ml was added and the mixture was added at 60 ° C. Stir for 5 hours. Then the pH is adjusted to 6.3 by addition of 6N HCl and the mixture is stirred at 60 ° C. for a further 1.5 hours. The precipitate is filtered off with suction and dried under high vacuum.
3.43 g of (34.2) was obtained as a colorless solid. The filtrate was extracted with dichloromethane, the organic phase was dried over sodium sulphate, filtered and the solvent removed in vacuo to give an additional 1.0 g of (34.2). (3
Total yield of 4.2): 4.43 g (66%) of colorless solid.

34b) N-Trityl-L-serine methyl ester (34.3) A solution of 10.75 g (38.56 mmol) trityl chloride in L-serine methyl ester hydrochloride in anhydrous THF at 0 ° C. 6 g (38.56 mmol) and triethylamine 7.8 g (77.12 mmol) are added and the solution is stirred at 0 ° C. for 4 hours and then at room temperature for 2 days. The solvent is removed in vacuo and the residue is partitioned between dichloromethane and 10% aqueous citric acid solution. The phases are separated and the organic phase is washed with water and dried over sodium sulphate. After filtration, the solvent is removed in vacuo and the residue is chromatographed on silica gel with heptane / ethyl acetate = 6/4. After concentrating the product fractions, (34.3) 8 g (5
8%).

34c) 3- [2-Methoxycarbonyl- (2S)-(tritylamino) ethyl] -2,4-dioxo-1,3,8-triazaspiro [4.5] decane-8-
Tertiary butyl carboxylate (34.4) 3.6 g of (34.2) (13.3) in 15 ml of anhydrous THF.
Solution of (7 mmol) (3 mmol) in 20 ml of anhydrous THF.
4.3) 3.72 g (10.3 mmol) and 3.5 g (13.34 mmol) triphenylphosphine are added to the solution. Diethyl azodicarboxylate (DEAD) 2.1
1 ml (13.37 mmol) is added to this solution and the reaction mixture is stirred at room temperature until the reaction is complete. The solvent is removed in vacuo and the residue is chromatographed on silica gel with heptane / ethyl acetate. After concentrating the product fraction (34.4)
6 g (95%) was obtained.

34d) 3-((2S) -amino-2-methoxycarbonylethyl) -2,4-dioxo-1,3,8
-Triazaspiro [4.5] decane-8-carboxylate tert-butyl (34.5) dichloromethane / methanol / trifluoroacetic acid = 9
5.5 / 3 / 1.5 4.6 g of (34.4) in 180 ml
A solution of (7.5 mmol) is stirred at room temperature for 10 minutes.
The reaction mixture is concentrated and the residue is chromatographed on silica gel. After concentrating the product fractions, 3.14 g (87%) of (34.5) was obtained.

34e) 3-((2S) -benzyloxycarbonylamino-2-methoxycarbonylethyl)-
2,4-Dioxo-1,3,8-triazaspiro [4.5]
Tert-Butyl decane-8-carboxylate (34.6) 2.08 g (16.1 mmol) diisopropylethylamine in 25 ml anhydrous DMF was added to 80 m anhydrous DMF.
3.14 g (8.48 mmol) of (34.5) in 1 and N
-Benzyloxycarbonyloxysuccinimide 2.
11 g (8.48 mmol) are added to the solution and the mixture is stirred for 3 hours at room temperature. The solvent is removed in vacuo and the residue is chromatographed on silica gel with heptane / ethyl acetate = 6/4. After concentrating the product fractions, (34.6) was obtained.

34f) Methyl (2S) -benzyloxycarbonylamino-3- (2,4-dioxo-1,3,8-triazaspiro [4.5] dec-3-yl) propionate hydrochloride (34.7) ) (34.6) 4.7 in 100 ml of 90% trifluoroacetic acid
A solution of g (9.3 mmol) is stirred at room temperature for 45 minutes. Trifluoroacetic acid is removed in vacuo and the residue is chromatographed on Sephadex LH20 using water / butanol / acetic acid = 43 / 4.3 / 3.5. The product fraction is concentrated and lyophilized. After adding dilute HCl and lyophilizing once again,
(34.7) 1.99 g [(34.5) starting from 53
%] Was obtained as a colorless solid.

34 g) 3- [8- (3- (1H-benzimidazol-2-ylamino) propionyl) -2,
Methyl 4-dioxo-1,3,8-triazaspiro [4.5] dec-3-yl]-(2S) -benzyloxycarbonylaminopropionate (34.11) (34.11) gives (15.2) As described in Example 15 for the synthesis of (15.3) from ().
It is synthesized by coupling 7) with (34.10).

34h) 3- [8- (3- (1H-benzimidazol-2-ylamino) propionyl) -2,
4-dioxo-1,3,8-triazaspiro [4.5] dec-3-yl]-(2S) -benzyloxycarbonylaminopropionic acid (34.12) (34.12) is (3.10) From (3.11) as described in Example 3 by cleaving the ester of (34.11). ES (+)-MS: 578 (M + H) ⁺

34i) Synthesis of (34.10) 3- (1H-Benzimidazol-2-ylamino) propionic acid (34.10) 34.10 is prepared by the following reaction scheme.

[0202]

[Chemical formula 119]

A) 3- [3- (2-Nitrophenyl) thiourea] propionic acid (34.8) Triethylamine (3.8 ml, 27.75 mmol) was added to D
2-Nitrophenyl isothiocyanate 5 g (27.75 mmol) and β-alanine 2.5 g in 80 ml MF
(27.75 mmol) and the mixture was added to
Stir until the reaction is complete. The solvent is removed in vacuo and the residue is partitioned between ethyl acetate and KHSO ₄ / K ₂ SO ₄ solution. The phases are separated and the organic phase is dried over sodium sulphate. After filtration, the solvent is removed in vacuo and the residue is chromatographed on silica gel. After concentrating the product fraction, (34.8) 5.
3 g (71%) was obtained.

B) 3- [3- (2-Aminophenyl) thioureido] propionic acid (34.9) Ammonia-saturated EtOH (34.8) in 410 ml.
5.3 g (19.7 mmol) of 10% Pd / C 6.4
Hydrogenate over 4 g at room temperature for 3 hours. The catalyst was filtered off, the filtrate was concentrated in vacuo and the residue [1.9 g of crude product of (34.9)] was used directly for the synthesis of (34.10).

C) 3- (1H-benzimidazole-
2-ylamino) propionic acid (34.10) (34.9) in 40 ml of ethanol, mercuric oxide 3.4
A mixture consisting of 4 g (14.79 mmol) and 50 mg of sulfur is heated under reflux for 5 hours. After filtration, the filtrate is concentrated and the residue is heated to reflux with 6N HCl for 1 hour, then the latter solution is freeze-dried. (3
4.10) Fraction 1 is obtained. The filter residue is leached with water several times and the combined aqueous phases are freeze-dried.
Fraction 2 of (34.10) is obtained. Fractions 1 and 2 are combined and water / butanol / acetic acid = 43 /
Chromatography on Sephadex LH 20 using 4.3 / 3.5. The product fraction is concentrated and lyophilized. (34.10) 340 mg [(3
8%] was obtained as a colorless solid starting from 4.8).

Example 35 3- [2- (4 (E or Z)-(3- (1H-benzimidazol-2-ylamino) propylidene) -2,5-
Dioxoimidazolidin-1-yl) acetylamino]
-(2S) -Benzyloxycarbonylaminopropionic acid ((E-35.8) or (Z-35.8), respectively) The synthesis was carried out by the following reaction sequence.

[0207]

Embedded image

35a) Methyl 3-amino-3- (dimethoxyphosphoryl) propionate (35.2) 10 g (30.19 mmol) Z-phosphonoglycine trimethyl ester (35.1) in 300 ml methanol.
Is hydrogenated over 10% Pd / C. After 1 hour, the catalyst is filtered off and the filtrate is concentrated in vacuo. (35.2)
4.6 g were obtained as crude product. This one is (3
It was used directly to synthesize 5.3).

35b) 3- (dimethoxyphosphoryl)
Methyl-3- (3-ethoxycarbonylmethylurea) propionate (35.3) 2.62 ml (23.4 mmol) ethyl acetate isocyanate are added to a solution of (35.2) in 20 ml DMF. After 16 hours at room temperature, another 0.262 ml (2.34 mmol) of ethyl isocyanate was added and the reaction mixture was stirred at room temperature for a further 2 hours. The solvent was removed in vacuo and the residue was washed with dichloromethane and KHSO ₄
/ K ₂ SO ₄ solution. The phases are separated and the organic phase is washed with water. The organic phase is dried over sodium sulphate, filtered and the filtrate is concentrated in vacuo and then (35.
3) 62 g [63% starting from (35.1)] were obtained.

35c) [4 (E or Z)-(3-third
Butoxycarbonylaminopropylidene) -2,5-dioxo-imidazolidin-1-yl] ethyl acetate ((E-35.4) or (Z-35.4) respectively) (35.3 in anhydrous EtOH (35.3)). ) 5.8 g (17.
Solution of 84 mmol) is added to a solution of 451 mg (18.8 mmol) of sodium in absolute EtOH. OPG
A solution of (35.9) prepared from β-alanine in analogy to Oel et al. Org. Synth. 1988, 67, 69 is added to the initial solution. After stirring for 3 hours at room temperature, the solvent is removed in vacuo and the residue is partitioned between water and diethyl ether. The phases are separated and the organic phase is dried over sodium sulphate. After filtration, the residue is converted to dichloromethane /
Chromatograph on silica gel using methanol = 99/1. (E- or Z-35.4) 2.
25 g and 1.95 g of (Z- or E-35.4) were obtained. Overall yield: (35.4) 4.2 g (69%).

35d) [4 (E or Z)-(3-aminopropylidene) -2,5-dioxoimidazolidin-1-yl] ethyl acetate trifluoroacetate (respectively (E-35 .5) or (Z-35.5)) (Z- or E-3 in 25 ml of 90% trifluoroacetic acid.
5.4) 2.25 g (6.6 mmol) of solution was added at room temperature to 1
Stir for hours. Trifluoroacetic acid is removed in vacuo and the residue diluted with water and the mixture freeze-dried. 2.2 g (94%) of (Z- or E-35.5) were obtained.

35e) Ethyl [4 (E or Z)-(3-isothiocyanatopropylidene) -2,5-dioxoimidazolidin-1-yl] acetate ((E-35.
6) or (Z-35.6)) (E-35.6) or (Z-35.6) is (11.
(E-35.5) or (Z-35.5), respectively, as described in Example 11 for the synthesis of (11.2) from 1).

35f) [4 (E or Z)-(3-
(1H-Benzimidazol-2-ylamino) propylidene) -2,5-dioxo-imidazolidin-1-yl] acetic acid hydrochloride ((E-35.7) or (Z-3, respectively)
(5.7)) (E-35.7) or (Z-35.7) is (11.
(E-35.6) or (Z-35.6), respectively, as described in Example 15 for the synthesis of (15.2) from 2).

35 g) 3- [2- (4 (E or Z)
-(3- (1H-benzimidazol-2-ylamino) propylidene) -2,5-dioxo-imidazolidin-1-yl) acetylamino]-(2S) -benzyloxycarbonylaminopropionic acid (each (E-3
(5.8) or (Z-35.8)) (E-35.8) or (Z-35.8) is (15.
(E-35.7) or (Z-35.7), respectively, as described in Example 15 for the synthesis of (15.3) from 2). (E-35.8) or (Z-35.8): ES (+)-MS:
550 (M + H) ⁺

Example 36 3- [2- (4 (Z or E)-(3- (1H-benzimidazol-2-ylamino) propylidene) -5-oxo-2-thioxoimidazolidin-1-yl) Acetylamino]-(2S) -benzyloxycarbonylaminopropionic acid ((Z-36) or (E-36), respectively)

[0216]

[Chemical 121] (Z-36) or (E-36) is synthesized as described in Example 35. In this case, it is reacted with methyl isocyanate methyl acetate instead of ethyl isocyanate ethyl acetate. The subsequent synthesis is performed in the same manner as in Example 35. (Z-36) or (E-36): ES (+)-MS: 5
66 (M + H) ⁺

Example 37 3- (4-E / Z- (4-guanidinocarbonylbenzylidene) -2,5-dioxoimidazolidin-1-yl)-(2S) -N-benzyloxyalanine (E / Z −
37.5) The synthesis was carried out by the following reaction sequence.

[0218]

[Chemical formula 122]

37a) 2-Isocyanate-Z-alanine tert-butyl ester (37.1) Z-Dap-Ot-Bu (1.6) 2.94 in 80 ml of methylene chloride.
A solution of g (10 mmol) is cooled to about 0 ° C. in an ice bath with 80 ml of a saturated solution of sodium bicarbonate with vigorous stirring. After adjusting the stirring method and separating the phases,
10.4 ml of a 1.93 molar solution of phosgene in toluene,
It is rapidly introduced into the organic phase and the mixture is brought to completion again with efficient stirring and external cooling. After a further 10 minutes, the phases are separated and the aqueous phase is washed with 2 ml of methylene chloride in each case.
Extract twice. The combined organic extracts are dried over anhydrous magnesium sulfate, filtered and the solvent removed in vacuo. About 3.0 g of colorless oil was obtained. This was used in the synthesis of (37.2) without further purification.

37b) N '-(dimethoxyphosphoryl)-(methoxycarbonyl) methylureido-N-
(2S) -benzyloxycarbonylamino-3-tert-butyl propionate (37.2) The amount of (37.1) obtained from (37a) was dissolved in about 30 ml of dichloromethane under a protective gas atmosphere of argon. Then, it was dissolved in about 50 ml of dichloromethane (3
5.2) 1.97 g are added at room temperature and with stirring. The reaction is complete after about 2 hours. The solution is washed first with 100 ml of a 2N solution of potassium hydrogensulfate and then with 100 ml of water. Then the organic phase is dried over anhydrous magnesium sulphate and filtered. After removing the solvent in vacuo, 4.6 g (89%) of pure (37.2) was obtained.

37c) E- or Z-3- (4- (4
-Methoxycarbonylbenzylidene) -2,5-dioxo-imidazolidin-1-yl) -2-N-benzyloxycarbonylaminopropionate t-butyl (37.
3) 1.55 g (3 mmol) of (37.2) are dissolved in about 8 ml of methanol and 0.6 ml (about 3.3 mmol) of a 30% solution of sodium methoxide in methanol are added.
0.59 g of methyl 4-formylbenzoate was added to this solution.
8 ml of a methanol solution containing (3.6 mmol) is gradually added (under argon protective gas and at room temperature with stirring).
Add dropwise. The reaction is complete after about 1 hour. The solution is concentrated in vacuo and the residue is taken up in ethyl acetate. The solution is washed with water, dried, filtered and concentrated. (3
1.6 g of an E / Z mixture of 7.3) was obtained.

Diastereomers can be separated by chromatography using ethyl acetate / n-heptane (2: 1) as eluent and silica gel as carrier material. 0.85 g of (Z-37.3) and 0.7 g of (E-37.3) were obtained.

37d) E- or Z-3- (4- (4-
Guanidinocarbonylbenzylidene) -2,5-dioxo-imidazolidin-1-yl)-(2S) -N-benzyloxycarbonylaminopropionate t-butyl (E- or Z-37.4 respectively) (Z-37. 3) 0.262 g (0.5 mmol) was dissolved in 5 ml of anhydrous tetrahydrofuran, and guazinine was dissolved in 0.5 ml.
148 g (2.5 mmol) are added and the mixture is heated under reflux for 20 hours. After removing the solvent in vacuo, the residue is chromatographed on silica gel using methanol / methylene chloride (1:10). (Z
-37.4) 0.05 g was obtained. (E-37.3)
Is similarly reacted with 1,2-dimethoxyethane as a solvent. 0.12 g of (E-37.4) was obtained.

37e) E- or Z-3- (4- (4-
Guanidinocarbonylbenzylidene) -2,5-dioxo-imidazolidin-1-yl)-(2S) -N-benzyloxycarbonylaminopropionic acid trifluoroacetate (E- or Z-37.5, respectively) (E-37 .4) 0.12 g is dissolved in ice-cold 90% trifluoroacetic acid (ca. 10 ml) and the solution is stirred under argon protective gas at room temperature for 1.5 hours. After removing the solvent in vacuo, the residue is chromatographed through RP 18 using methanol / water.
The product fraction was concentrated and (E-37.5).
06 g were obtained. In the same manner (Z-37.4) 0.05 g
To give (Z-37.5) 0.02 g.

Example 38 3- (4-E / Z- (4- (3,4,5,6-tetrahydropyrimidin-2-yl) aminocarbonylbenzylidene) -2,5-dioxoimidazolidin-1- Ill)-
(2S) -N-benzyloxycarbonylalanine (E /
Z-38.4) The synthesis was carried out by the following reaction sequence.

[0226]

Embedded image

38a) E- or Z-3- (4-((2
-Phenylthio) ethyloxycarbonylbenzylidene) -2,5-dioxoimidazolidin-1-yl)-
Tert-Butyl (2S) -N-benzyloxycarbonylaminopropionate (E- or Z-38.1, respectively) In the same manner as in the reaction (37c), (37.2) 0.259 g
(0.5 mmol) and 4-formylbenzoic acid (2-
From 0.172 g (0.6 mmol) of phenylthio) ethyl, 0.157 g of (Z-38.1), which can be separated individually by chromatography, and (E-3).
8.1) 0.153 g was obtained (total yield: about 91%)

38b) E- or Z-3- (4- (carboxylbenzylidene) -2,5-dioxoimidazolidin-1-yl) -2-N-benzyloxycarbonylaminopropionate tert-butyl (each E -Or Z-
38.2) (Z-38.1) 0.1155 g (0.24 mmol),
Dissolve in 5 ml of dry methylene chloride and add 0.098 g (0.4 mmol) of 65% meta-chloroperbenzoic acid.
The reaction is complete after 1.5 hours. The methylene chloride solution is washed with sodium acid sulfite (about 10% strength) and then water. After drying over magnesium sulphate, filtering and removing the solvent, 0.15 g of phenylsulfonylethyl ester is obtained. This compound was treated without further treatment with 8 ml dioxane, 1.4 m methanol.
1 and 0.19 ml of 1N NaOH are introduced.
After 16 hours the solvent was removed in vacuo and the residue was
Chromatograph on silica gel using methylene chloride / methanol (95: 5). Yield: (Z-
38.2) 0.033 g. (E-38.1) 0.157g
From (0.24 mmol), in a similar manner (E-38.
2) 0.051 g was obtained.

38c) 3- (4-E / Z- (4- (3,
4,5,6-Tetrahydropyrimidin-2-yl) aminocarbonylbenzylidene) -2,5-dioxoimidazolidin-1-yl)-(2S) -N-benzyloxycarbonylaminopropionate tert-butyl (E / Z-38.
3) Protocol for synthesizing 11.6 (Protocol 11
(E-38.2) 0.05 in the same manner as f) in dimethylformamide in the presence of diisopropylethylamine.
g (0.1 mmol) and 2-amino-3,4,5,6-
0.01 g (0.1 mmol) of tetrahydropyrimidine are reacted with the corresponding amount of TOTU (0.033 g).
Conventional treatment gives 0.06 g of (E-38.3). This compound can be reacted without further purification. From 0.03 g of (Z-38.2), 0.025 g of crude product of (Z-38.3) in a similar manner.
I got

38d) 3- (4-E / Z- (4- (3,
4,5,6-Tetrahydropyrimidin-2-yl) aminocarbonylbenzylidene) -2,5-dioxoimidazolidin-1-yl)-(2S) -N-benzyloxycarbonylamino-propionic acid (E / Z- 38.4) 0.055 g of (E-38.3) is stirred in 2 ml of 90% trifluoroacetic acid for 2 hours with ice cooling. The solvent was removed in vacuo and the residue lyophilized to (E-3
8.4) 0.02 g was obtained. From 0.02 g of (Z-38.3), 0.012 g of (Z-38.4) was obtained in the same manner.

The inhibition of bone resorption by the novel compounds can be measured, for example, using the osteoclast resorption test (“PIT test”), as in WO 95/32710. The test methods used to determine the antagonistic effect of the novel compounds on the α _v β ₃ vitronectin receptor are described below.

Test Method 1: Inhibition of binding of human vitronectin (Vn) to human vitronectin receptor (VnR) α _v β ₃ : ELIS
A-Test. (In the list of test results, test method 1
Is abbreviated as Vn / VnR)

1. Purification of human vitronectin Human vitronectin was isolated from human plasma and the method of Yatoyo et al. [Cell Structure and Function, 19
88, 23, 281-292] using affinity chromatography.

2. Human vitronectin receptor (α
Purification of _v β ₃ ) Human vitronectin receptor can be obtained by the method of Pytela et al. [Meth
ods Enzymol. 1987, 144, 475] using human placenta. Human vitronectin receptor α _v β ₃
Can also be isolated from some cell lines (eg human embryonic kidney cell line 293 cells) that have been cotransfected with DNA sequences for the two subunits of the vitronectin receptor α _v and β ₃ . These subunits are extracted with octyl glycoside and then chromatographed on concanavalin A, heparin-sepharose and S-300.

3. Monoclonal Antibodies Murine monoclonal antibodies specific for the β ₃ subunit of the vitronectin receptor were prepared by the method of Newman et al. [Blood, 1985, 227-232] or by a similar method. Rabbit Fab anti-mouse Fc conjugate with horseradish peroxidase (anti-mouse Fc HRP)
Was obtained from Pel Freeze (Catalog No. 715 305-1).

4. ELISA test Nunc Maxisorb 96-well microtiter plates were
A solution of human vitronectin (0.002 mg / m 2) in PBS (phosphate-buffered sodium chloride solution) overnight at 4 ° C.
l, 0.05 ml / well). Plate, PB
Washed twice with S / 0.05% Tween 20 and Tris-HCl (50 mM), NaCl (100 mM), MgC
l ₂ (1 mM), CaCl ₂ (1 mM), MnCl ₂ (1 mM)
Bovine serum albumin (pH7) (BSA, 0.5%,
Incubate with RIA grade or better (6
0 minutes) to block. 2 x 10 ^-12 ~
A solution of known inhibitor and test substance at a concentration of 2 × 10 ⁻⁶ mol / l was added to the test buffer [Tris-HCl (50 mM.
/ Liter), NaCl (100 mM), MgCl ₂ (1 m
M), CaCl ₂ (1 mM), MnCl ₂ (1 mM) (pH 7)
BSA in (0.5%, RIA grade or better)]. The blocked plates were emptied and in each case 0.025 ml of this solution containing a defined concentration of known inhibitor or test substance (2 × 10 ⁻¹² to 2 × 10 ⁻⁶ ) was added to each well. Add. A solution of vitronectin receptor in test buffer (0.0
0.025 ml (3 mg / ml) is pipetted into each well of the plate and then the plate is incubated on a shaker at room temperature for 60-180 minutes. In the meantime, a solution of a murine monoclonal antibody specific for the β ₃ subunit of the vitronectin receptor (6 ml
/ Plate) in test buffer (0.001)
5 mg / ml). A second rabbit antibody showing anti-mouse Fc HRP antibody conjugate was added to this solution (0. 6 stock solutions per 6 ml murine monoclonal anti-β ₃ antibody solution).
001 ml) and this mixture of murine anti-β ₃ antibody and rabbit anti-mouse FcHRP antibody conjugate is incubated while the receptor / inhibitor incubation is in progress. The test plate is washed 4 times with a PBS solution containing 0.05% Tween 20 and 0.05 ml of the antibody mixture is pipetted into each well of the plate in each case, which is then 60-180. Incubate for minutes. The plates were washed 4 times with PBS / 0.05% Tween-20 and then o-phenylenediamine 0.67 mg / m 2.
PBS solution containing 1 and 0.012% H ₂ O ₂ .
Develop with 05 ml / well. Instead of doing so, o-phenylenediamine was added to Na ₃ PO ₄ (50 mM).
And a buffer containing citric acid (0.22 mM) (pH
5) can be used in. Color development is 1N H ₂ SO
Stop using ₄ (0.05 ml / well). The absorption of each well is measured at 492-405 nm and the data evaluated using standard methods.

Test Method 2: Inhibition of Binding of Kistrin to Human Vitronectin Receptor (VnR) α _v β ₃ : ELISA Test (Test Method 2 is Abbreviated as Kistrin / VnR in the List of Test Results) 1. Kistrin Purified Kistrin of Proc. Natl. Acad. Sci. USA 1989, 87,
2471-2475 and PROTEINS: Structure, Function and
Purified using the method of Dennis et al., Described in Genetics 1993, 15, 312-321. 2. Purification of human vitronectin receptor (α _v β ₃ ) See Test Method 1. See 3. Monoclonal antibody test method 1.

4. ELISA Test The ability of substances to inhibit the binding of kextrin to the vitronectin receptor can be demonstrated using an ELISA test. For this purpose, Nunc 96-well microtiter plates were loaded with PROTEINS: Structure, Fun.
ction and Genetics 1993, 15, 312-321 and coated with a solution of xistrin (0.002 mg / ml) by the method of Dennis et al. Subsequent experimental runs of the ELISA test are as described in 4 of Test Method 1.

Test results:

[Table 1]

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification number Office reference number FI Technical display location A61K 31/435 ABS A61K 31/435 ABS ABX ABX ACV ACV ADP ADP ADS ADS AED AED AED 31/505 ADU 31 / 505 ADU C07D 233/76 C07D 233/76 403/12 233 403/12 233 405/14 233 405/14 233 471/04 107 471/04 107A 471/10 103 471/10 103 (72) Inventor Hans Ulrich Schyuterz, Federal Republic of Germany 65929 Frankfurt. Johannes Alley 18 (72) Inventor Deni Karniet France 91460 Marx. Ave Ndou Retanneuf 10 (72) Inventor Jean-Francois Grouvest 77410 Clay Sui. Liyudura Vibron 12 (72) Inventor Tom Gaydeck 94611 Oakland, Calif., USA. Chelsea Drive 2838 (72) Inventor Robert McDowell 94114 San Francisco, Calif., USA. Chachi Street 1264

Claims (8)

[Claims] 1. A compound of the formula I And a physiologically acceptable salt thereof. In the above formula, W is R ¹ -A-B-D-C (R ¹⁶ ), R ¹ -A-B-D-
C (R ¹⁶ ) = C, embedded image [Wherein the ring system Is one or more saturated or unsaturated containing 1 or 2 heteroatoms from the group N, O and S and substituted by 1 to 3 substituents from R ^16. Y or substituted with one or two doubly bonded O or S]; Y
Is, C = O, C = S or -CH ₂ -; Z is, N
(R ⁰ ), O, S or —CH ₂ —; A is a single direct bond, (C ₁ -C ₈ ) -alkanediyl, —NR ² —N
^{= CR 2 -, - NR 2} -C (O) -NR 2 -, - NR 2 -C
(O) O -, - NR 2 -C (O) -S -, - NR 2 -C (S) -
^{NR 2 -, - NR 2 -C} (S) -O -, - NR 2 -C (S) -
^{S -, - NR 2 -S (} O) n -NR 2 -, - NR 2 -S (O) n
^{-O -, - NR 2 -S (} O) n -, (C 3 -C 12) - ^{cycloalkanediyl, -C≡C -, - NR 2 -C} (O) -, - C
^{(O) -NR 2 -, -} (C 5 -C 14) - arylene -C (O) -
^{NR 2 -, - O-, S} (O) n -, (C 5 -C 14) - arylene -, - CO -, (C 5 -C 14) - arylene -CO-,
_{^{-NR 2 -, - SO 2 -NR}} 2 -, - C (O) O -, - O-
C (O) -, - N = CR 2 -, - R 2 C = N -, - CR 2 =
CR ³ - or - (C ₅ -C ₁₄₎ - arylene -S (O) _n -
[These radicals may in each case be substituted by NR ² and / or 1 or 2
Optionally substituted by (C ₁ -C ₈ ) -alkanediyl]; and B is a single direct bond, (C ₁ -C ₈ ).
- alkanediyl, (C ₅ -C ₁₀₎ - arylene, (C ₃ -
C ₈₎ - cycloalkyl alkanediyl, -C≡C -, - NR
^{2 -, - C (O)} -, NR 2 -C (O) -, - C (O) -NR 2
^{-, - NR 2 -C (O} ) -NR 2, -NR 2 -C (S) -NR 2
-, -OC (O)-, -C (O) O-, -S (O)-, -S
_{(O) 2 -, - S} (O) -NR 2 -, - S (O) 2 -NR 2 -, -
^{NR 2 -S (O) -,} - NR 2 -S (O) 2 -, - O -, - S
- or -CR ² = CR ³ - [these groups, in each case, one or two (C ₁ -C ₆₎ - alkanes may be substituted by diyl] a or one or Contains 2 nitrogen atoms and 1 or 2
(C ₁ -C ₆ ) -Alkyl or a 5- or 6-membered saturated or unsaturated ring divalent radical optionally substituted by double-bonded oxygen or sulfur; One direct bond, (C ₁ -C ₈ ) -alkanediyl, (C ₅ -C ₁₀ ).
- ^{arylene, -O -, - NR 2 -} , - CO-NR 2 -,
^{-NR 2 -CO -, - NR 2} -C (O) -NR 2 -, - NR 2
^{-C (S) -NR 2 -,} - OC (O) -, - C (O) O -, -
CO-, -CS-, -S (O)-, -S (O) _2- , -S
^{_{(O) 2 -NR 2 -,}} - NR 2 -S (O) -, - NR 2 -S (O)
_{2 -, - S -, -} CR 2 = CR 3 -, - C≡C -, - NR 2
^{-N = CR 2 -, - N} = CR 2 -, - R 2 C = N- or -CH (OH) - [these groups may in each case one or two (C ₁ -C ₈ ) -Alkanediyl, -C
R ² = CR ³ — or (C ₅ -C ₆ ) -arylene may be substituted]; and E is a single direct bond,
(C ₁ -C ₆₎ - alkanediyl, (C ₂ -C ₆₎ - alkenediyl, (C ₂ -C ₆₎ - alkynediyl, phenylene, phenylene - (C ₁ -C ₃₎ - alkanediyl or (C ₁ - C ₃₎
-Alkanediyl-phenylene; F is as defined as D; G is L is C (R ¹⁶ ) or N; R ⁰ is H,
(C ₁ -C ₈ ) -Alkyl, optionally substituted by one or more than one fluorine, (C _3- )
C ₁₂₎ - cycloalkyl, (C ₃ -C ₁₂₎ - cycloalkyl - (C ₁ -C ₈₎ - alkyl, (C ₅ -C ₁₄₎ - aryl, (C
_5- C ₁₄ ) -aryl- (C ₁ -C ₈ ) -alkyl or (C ₁
-C ₈₎ - alkyl -C (O) -, (C 3 -C 12) - cycloalkyl -C (O) -, (C 3 -C 12) - cycloalkyl - (C
₁ -C ₆₎ - alkyl _{-C (O), (C 5} -C 14) - aryl -
C (O) - or (C ₅ -C ₁₄₎ - aryl - (C ₁ -C ₆₎ -
Alkyl-C (O) [wherein the alkyl group can be substituted by one or more than one fluorine]; R
^{1, R 2 -C (= NR 2} ) NR 2 -, R 2 R 3 N-C (= N
R ² ) −, R ² R ³ N—C— (═NR ² ) —NR ² or optionally 1 to 4 heteroatoms selected from the group of N, O and S. And in some cases 1
4-14-, which may be substituted by one or more substituents from the group of R ¹² , R ¹³ , R ¹⁴ and R ¹⁵
Membered mono- or polycyclic aromatic or non-aromatic ring system; R ² and R ³ independently of one another are substituted by H, optionally one or more than one fluorine. Optionally, (C ₁ -C ₁₀ ) -alkyl, (C ₃ -C ₁₂ ) -cycloalkyl, (C ₃ -C ₁₂ ) -cycloalkyl- (C _1-
C ₈₎ - alkyl, (C ₅ -C ₁₄₎ - aryl, (C ₅ -C ₁₄₎
- aryl - (C ₁ -C ₈₎ - alkyl, H ₂ N, R ⁸ ONR
^{9, R 8 OR 9, R} 8 OC (O) R 9, R 8 - (C 5 -C 14) - aryl ^{-R 9, R 8 R 8 NR} 9, HO- (C 1 -C 8) - alkyl ^{-NR 8 R 9, R 8 R} 8 NC (O) R 9, R 8 C (O) NR
⁸ R ⁹ , R ⁸ C (O) R ⁹ , R ⁸ R ⁸ NC (= NR ⁸ )-, R ⁸ R
^{8 N-C (= NR 8} ) -NR 8 - or (C ₁ -C ₁₈₎ - alkylcarbonyloxy - (C ₁ -C ₆₎ - alkoxy ^{carbonyloxy; R 4, R 5, R} 6 and R ⁷ Independently of each other, H, fluorine, OH, (C ₁ -C ₈ ) -alkyl, (C ₃ -C
₁₂₎ - cycloalkyl, (C ₃ -C ₁₂₎ - cycloalkyl -
(C ₁ -C ₈ ) -Alkyl, or R ⁸ OR ⁹ , R ⁸ SR ⁹ , R
_{^{8 CO 2 R 9, R 8}} OC (O) R 9, R 8 - (C 5 -C 14) - aryl ^{-R 9, R 8 N (R} 2) R 9, R 8 R 8 NR 9, R 8 N (R ² )
C (O) OR ⁹ , R ⁸ S (O) _n N (R ² ) R ⁹ , R ⁸ OC (O) N
(R ² ) R ⁹ , R ⁸ C (O) N (R ² ) R ⁹ , R ⁸ N (R ² ) C (O) N
(R ² ) R ⁹ , R ⁸ N (R ² ) S (O) _n N (R ² ) R ⁹ , R ⁸ S (O) _n
R ⁹ , R ⁸ SC (O) N (R ² ) R ⁹ , R ⁸ C (O) R ⁹ , R ⁸ N (R
² ) C (O) R ⁹ or R ⁸ N (R ² ) S (O) _n R ⁹ ; R
⁸ is H, (C ₁ -C ₈ ) -alkyl, (C ₃ -C ₁₂ ) -cycloalkyl, (C ₃ -C ₁₂ ) -cycloalkyl- (C ₁ -C ₈ ).
- alkyl, (C ₅ -C ₁₄₎ aryl or (C ₅ -C ₁₄₎ -
Aryl- (C ₁ -C ₈ ) -alkyl [wherein the alkyl group can be substituted by one or more than one fluorine]; R ⁹ is a single direct bond or (C ₁
-C ₈₎ - be a alkanediyl; R ¹⁰ is, C (O) R ^11,
4-8-containing 1, 2, 3 or 4 heteroatoms from the group of C (S) R ¹¹ , S (O) _n R ¹¹ , P (O) R ¹¹ _n or N, O and S A membered saturated or unsaturated heterocycle;
R ¹¹ is OH, (C ₁ -C ₈ ) -alkoxy, (C ₅ -C ₁₄ ).
- aryl - (C ₁ -C ₈₎ - alkoxy, (C ₅ -C ₁₄₎ -
Aryloxy, (C ₁ -C ₈₎ - alkylcarbonyloxy - (C ₁ -C ₄₎ - alkoxy, (C ₅ -C ₁₄₎ - aryl - (C ₁ -C ₈₎ - alkylcarbonyloxy - (C ₁ -C ₆₎
- alkoxy, NH _2, mono- - or di (C ₁ -C ₈ - alkyl) amino, (C ₅ -C ₁₄₎ - aryl - (C ₁ -C ₈₎ -
Alkylamino, (C ₁ -C ₈₎ - dialkylaminocarbonyloxy methyloxy, (C ₅ -C ₁₄₎ - aryl - (C ₁ -
C ₈₎ - dialkylaminocarbonyl methyloxy or
(C ₅ -C ₁₄₎ - aryl amino or L- or D- amino ^{acid; R 12, R 13, R} 14 and R ^15, independently of one another, H, from 1 or 1 as the case (C ₁ -C ₁₀ ) -Alkyl, (C ₃ -C ₁₂ ) -Cycloalkyl, (C ₃ -C ₁₂ ) -Cycloalkyl- (C ₁ -C ₈ )-, which may be substituted with a large amount of fluorine. Alkyl, (C ₅ -C ₁₄ )-
Aryl, (C ₅ -C ₁₄₎ - aryl - (C ₁ -C ₈₎ - ^{_{alkyl, H 2 N, R 8 ONR}} 9, R 8 OR 9, R 8 OC (O)
^{R 9, R 8 R 8 NR} 9, R 8 - (C 5 -C 14) - aryl -
_{^{R 9, HO- (C 1 -C}} 8) - alkyl ^{-N (R 2) R 9,} R 8 N
(R ² ) C (O) R ⁹ , R ⁸ C (O) N (R ² ) R ⁹ , R ⁸ C (O)
^{R 9, R 2 R 3 N} -C (= NR 2) -NR 2 -, R 2 R 3 N-C
(= NR ² ), ═O or ═S and the groups R ^{12 to} R ¹⁵
The two adjacent substitutions from are taken together as --OCH _{2
O -, - OCH 2 CH 2} O- or -OC (CH ₃₎ can be ₂ O- in which; R ¹⁶ is, H, optionally substituted by a number of fluorine than 1 or 1 Good (C ₁
-C ₁₀₎ - alkyl, (C ₃ -C ₁₂₎ - cycloalkyl,
(C ₃ -C ₁₂₎ - cycloalkyl - (C ₁ -C ₈₎ - alkyl, (C ₅ -C ₁₄₎ - aryl, (C ₅ -C ₁₄₎ - aryl -
(C ₁ -C ₈₎ - alkyl, (C ₂ -C ₂₀₎ - alkenyl or (C ₂ -C ₁₀₎ - alkynyl; m is 1, 2,
3, 4, 5 or 6; n is 1 or 2;
p and q are, independently of each other, 0 or 1; provided that R ¹ -A-B-D-C (R ¹⁶ ) or R ¹ -A-B-
^{D-C (R 16) =} C is ^{R 1 -K-C (R 16} ) or R ¹ -K-
In ^{CH = C (R 16 = H} ) [In this case, R ¹ is, X-NH-C (= NH) - (CH 2) p, X 1 -NH-
(CH ₂ ) _p or 4-imidazolyl-CH _2- (p is 0 to
X may be hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylcarbonyl, (C ₁ -C ₆ ) -alkoxycarbonyl,
(C ₁ -C ₁₈ ) -Alkylcarbonyloxy- (C ₁ -C ₆ ).
- alkoxycarbonyl, (C ₆ -C ₁₄₎ - arylcarbonyl, (C ₆ -C ₁₄₎ - aryloxycarbonyl, (C
₆ -C ₁₄₎ - aryl - (C ₁ -C ₆₎ - alkoxycarbonyl, hydroxyl, (C ₁ -C ₆₎ - alkoxy, (C ₆ -C
₁₄ ) -Aryl- (C ₁ -C ₆ ) -alkoxy or amino (the aryl group in X is a pure carbocycle optionally substituted by one or more substituents) And X ¹ is (C ₄ -C ₁₄ ) -arylcarbonyl, (C ₄ —
C ₁₄₎ - aryloxycarbonyl, (C ₄ -C ₁₄₎ - aryl - (C ₁ -C ₆₎ - alkoxycarbonyl, (C ₄ -
C ₁₄₎ - aryl - (C ₁ -C ₆₎ - alkoxy or R '
-NH-C (= N-R ") (wherein R'and R" independently of ^{one another} have the meaning of X and the aryl group in X1 is optionally one or one. Is a pure carbocycle optionally substituted with more substituents) and K is (C ₁ -C ₆ ) -alkanediyl, (C ₃ -C ₇ ) -cycloalkanediyl, phenylene, Phenylene- (C ₁ -C
₆ ) -alkanediyl, (C ₁ -C ₆ ) -alkanediylphenylene, phenylene- (C ₂ -C ₆ ) -alkenediyl or containing 1 or 2 nitrogen atoms and 1 or 2 (C _1- C ₆ ) -Alkyl or 5- or 6-, optionally substituted by double-bonded oxygen or sulfur
Member of a saturated or unsaturated ring divalent group]. 2. W is R ¹ -A-B-D-C (R ¹⁶ ), R ¹
-A-B-D-C (R ¹⁶ ) = C, embedded image [Wherein the ring system Contains 1 or 2 heteroatoms from the group N and O, may be 1 saturated or unsaturated and R
Optionally substituted by 1 or 2 substituents from ¹⁶ ]; Y is C = O, C = S or -CH ₂
- and; Z is, -N (R ^0), O or -CH ₂ -; A is a single direct bond, (C ₁ -C ₆₎ - alkanediyl, -NR ² -N = ^{CR 2 -, - NR 2 -C} (O) -NR 2
^{-, - NR 2 -C (O} ) O -, - NR 2 -C (O) S -, - N
^{R 2 -C (S) -NR 2} -, - NR 2 -C (S) -O -, - N
^{R 2 -C (S) S -} , - NR 2 -S (O) n -NR 2 -, - NR
_{^{2 -S (O) n -O -}} , - NR 2 -S (O) n -, (C 3 -C 8) -
Cycloalkanediyl, -C≡C-, -NR ² -C (O)
-, - C (O) -NR 2 -, - (C 5 -C 12) - arylene -
^{C (O) -NR 2 -,} - O -, - S (O) n -, - (C 5 -
C ₁₂₎ - arylene -, - CO -, - ( C 5 -C 12) - arylene ^{-CO -, - NR 2 -,} - SO 2 -NR 2, -C
(O) O -, - O -C (O) -, - N = CR 2 -, - R 2 C =
^{N -, - CR 2 = CR} 3 -, - (C 5 -C 12) - arylene -S (O) _n - [these groups, and in each case may be substituted by NR ² ( Or) optionally substituted by one or two (C ₁ -C ₈ ) -alkanediyl]; B is a single direct bond, (C ₁ -C ₆ ) -alkanediyl, (C ₅ -C ₈ ) -Arylene, (C ₃ -C ₈ ) -Cycloalkanediyl, -C≡C
^{-, - NR 2 -, -} C (O) -, - NR 2 -C (O) -, - C
^{(O) -NR 2 -, -} NR 2 -C (O) -NR 2 -, - S (O)
_{-, - S (O) 2} -, - S (O) -NR 2 -, - S (O) 2 -N
^{R 2 -, - NR 2 -S} (O) -, - NR 2 -S (O) 2 -, - O
-, --CR ² ═CR ^3- [these groups may in each case be substituted by ₁ or 2 (C ₁ -C ₆ ) -alkanediyl]; One direct bond, (C ₁ -C ₈ ) -alkanediyl, (C ₅ -C ₈ )-
^{Arylene, -O -, - NR 2 -} , - CO-NR 2 -, -
^{NR 2 -CO -, - NR 2} -C (O) -NR 2, -NR 2 -C
^{(S) -NR 2 -, -} OC (O) -, - C (O) O -, - CO
-, -CS-, -S (O)-, -S (O) _2- , -S (O) _2-
^{NR 2 -, - NR 2 -S} (O) -, - NR 2 -S (O) 2 -, -
^{S -, - CR 2 = CR} 3 -, - C≡C -, - NR 2 -N =
^{CR 2 -, - N = CR} 2 - or -R ² C = N-[these groups, in each case, one or two
(C ₁ -C ₆₎ - alkanediyl, -CR ² = CR ³ - or
(C ₅ -C ₆₎ - may be substituted by arylene]
E is a single direct bond, (C ₁ -C ₄ ) -alkanediyl, (C ₂ -C ₄ ) -alkenediyl, (C ₂ -C ₄ )-
Alkynediyl, phenylene, phenylene - (C ₁ -C ₂₎
- alkanediyl or (C ₁ -C ₂₎ - be a alkanediyl phenylene; F is are as defined as D;
G is L is C (R ¹⁶ ), or N; R ⁰ is H,
(C ₁ -C ₆ ) -alkyl, (C ₃ -C ₈ ) -cycloalkyl,
(C ₃ -C ₈₎ - cycloalkyl - (C ₁ -C ₆₎ - alkyl,
(C ₅ -C ₁₂₎ - aryl, (C ₅ -C ₁₂₎ - aryl - (C ₁
-C ₆₎ - alkyl, (C ₁ -C ₈₎ - alkyl -C (O),
(C ₃ -C ₈₎ - cycloalkyl _{-C (O), (C 3} -C 8) - cycloalkyl - (C ₁ -C ₄₎ - alkyl _{-C (O), (C 5} -
C ₁₂₎ - aryl--C (O) or (C ₅ -C ₁₂₎ - aryl - (C ₁ -C ₄₎ - alkyl -C (O) [alkyl groups, 1
Or may be substituted by more than one fluorine]; R ¹ is R ² -C (= NR ² ) NR ^3- , R ² R ³
N-C (= NR ² )-, R ² R ³ N-C (= NR ² ) -NR ² or optionally 1 to 4 different seeds from the group N, O and S. Also and optionally one or more than one R ¹² , R ¹³ , R ¹⁴ and R ¹⁵
4-10 optionally substituted by a substituent from the group
A -membered mono- or polycyclic aromatic or non-aromatic ring system; R ² and R ³ , independently of one another, are H, optionally one or more than one fluorine. Optionally substituted by (C ₁ -C ₈ ) -alkyl, (C ₃ -C ₈ ) -cycloalkyl, (C ₃ -C ₈ ) -cycloalkyl- (C ₁ -C
₆₎ - alkyl, (C ₅ -C ₁₂₎ - aryl, (C ₅ -C ₁₂₎ -
Aryl - (C ₁ -C ₆₎ - alkyl, H ₂ N, R ⁸ ON
^{R 9, R 8 OR 9,} R 8 OC (O) R 9, R 8 - (C 5 -C 12) -
Aryl ^{-R 9, R 8 R 8 NR} 9, HO- (C 1 -C 8) - alkyl ^{-NR 8 R 9, R 8 R} 8 NC (O) R 9, R 8 C (O) NR 8
^{R 9, R 8 C (O} ) R 9, R 8 R 8 N-C (= NR 8) -, R 8 R 8
^{N-C (= NR 8)} -NR 8 - or (C ₁ -C ₁₀₎ - alkylcarbonyloxy - (C ₁ -C ₄₎ - alkoxycarbonyl ^{carbonyloxy; R 4, R 5, R} 6 and R ⁷ , Independently of each other, H, fluorine, OH, (C ₁ -C ₈ ) -alkyl, (C ₅ -C
₁₂₎ - cycloalkyl, (C ₅ -C ₁₂₎ - cycloalkyl -
(C ₁ -C ₈ ) -Alkyl or R ⁸ OR ⁹ , R ⁸ SR ⁹ , R ^{8
_{CO 2 R 9, R 8 OC}} (O) R 9, R 8 - (C 5 -C 12) - aryl ^{-R 9, R 8 N (R} 2) R 9, R 8 R 8 NR 9, R 8 N (R ² ) C
(O) OR ⁹ , R ⁸ S (O) _n N (R ² ) R ⁹ , R ⁸ OC (O) N
(R ² ) R ⁹ , R ⁸ C (O) N (R ² ) R ⁹ , R ⁸ N (R ² ) C (O) N
(R ² ) R ⁹ , R ⁸ N (R ² ) S (O) _n N (R ² ) R ⁹ , R ⁸ S (O) _n
R ⁹ , R ⁸ SC (O) N (R ² ) R ⁹ , R ⁸ C (O) R ⁹ , R ⁸ N (R
² ) C (O) R ⁹ , R ⁸ N (R ² ) S (O) _n R ⁹ ; R ⁸ is
_{H, (C 1 -C 6)} - alkyl, (C ₅ -C ₁₂₎ - cycloalkyl, (C ₅ -C ₁₂₎ - cycloalkyl - (C ₁ -C ₆₎ - alkyl, (C ₅ -C ₁₂ ) -Aryl or (C ₅ -C ₁₂ ) -aryl- (C ₁ -C ₆ ) -alkyl [wherein the alkyl group may be substituted by one or more than one fluorine]; and R ⁹ is , A single direct bond or (C ₁ -C ₆ ) -alkanediyl; R ¹⁰ is C (O) R ¹¹ , C (S)
R ¹¹ , S (O) _n R ¹¹ , P (O) R ¹¹ _n or N, O and S
A 4- to 8-membered saturated or unsaturated heterocycle containing 1, 2, 3 or 4 heteroatoms from the group of R;
¹¹ is OH, (C ₁ -C ₆ ) -alkoxy, (C ₅ -C ₁₂ )-
Aryl - (C ₁ -C ₆₎ - alkoxy, (C ₅ -C ₁₂₎ - aryloxy, (C ₁ -C ₆₎ - alkylcarbonyloxy - (C ₁ -C ₄₎ - alkoxy, (C ₅ -C ₁₂ ) -Aryl-
(C ₁ -C ₆ ) -Alkylcarbonyloxy- (C ₁ -C ₆ )-
Alkoxy, NH _2, mono- - or di (C ₁ -C ₆ - alkyl) amino, (C ₅ -C ₁₂₎ - aryl - (C ₁ -C ₆₎ - alkylamino or (C ₁ -C ₆₎ - dialkyl Aminocarbonylmethyloxy; R ¹² , R ¹³ , R ¹⁴ and R
¹⁵ may, independently of one another, be substituted by H, optionally one or more than one fluorine (C _1-
C ₈₎ - alkyl, (C ₃ -C ₈₎ - cycloalkyl, (C ₃ -
C ₈₎ - cycloalkyl - (C ₁ -C ₆₎ - alkyl, (C ₅ -
C ₁₂₎ - aryl, (C ₅ -C ₁₂₎ - aryl - (C ₁ -C ₆₎
- ^{_{alkyl, H 2 N, R 8 ONR}} 9, R 8 OR 9, R 8 OC
^{(O) R 9, R 8} - (C 5 -C 12) - aryl -R ^9, R ⁸ R ⁸ N
_{^{R 9, HO- (C 1 -C}} 8) - alkyl ^{-N (R 2) R 9,} R 8 N
(R ² ) C (O) R ⁹ , R ⁸ C (O) N (R ² ) R ⁹ , R ⁸ C (O)
^{R 9, R 2 R 3 N} -C (= NR 2) -, R 2 R 3 N-C (= N
R ³⁾ -NR ² -, a = O or = S and the radicals R ¹² ~
Two adjacent substitutions from R ¹⁵ are also taken together to form -O.
_{CH 2 O -, - OCH 2} CH 2 O- or -OC (CH _{3) 2}
May be O--; R ¹⁶ may be substituted by H, optionally one or more than one fluorine
(C ₁ -C ₈ ) -alkyl, (C ₃ -C ₈ ) -cycloalkyl,
(C ₃ -C ₈₎ - cycloalkyl - (C ₁ -C ₆₎ - alkyl,
(C ₅ -C ₁₂₎ - aryl, (C ₅ -C ₁₂₎ - aryl - (C ₁
-C ₆₎ - alkyl, (C ₂ -C ₈₎ - alkenyl, or (C ₂
-C ₈₎ - alkynyl; m is located at 3, 4 or 5; n is 1 or 2; and p and q has the formula of claim 1, wherein independently of one another are 0 or 1 Compounds of I and physiologically acceptable salts thereof. 3. W is R¹-A-B-D-C (R¹⁶), R¹−
A-B-D-C (R¹⁶) = C orY is C = C, C = S or -CH_Two-
R; Z is N (R⁰) Or -CH_Two-Is; A is a single
Direct bond, (C₁-C₆) -Alkanediyl, -NR^Two−
N = CR^Two-, -NR^Two-C (O) -NR^Two-, -NR^Two-C
(O) O-, -NR^Two-C (O) S-, -NR^Two-S (O)_n−
NR^Two-, -NR^Two-S (O)_n-, (C_Three-C₆) -Cycloa
Lucandiyl, -C≡C-, -NR^Two-C (O)-, -C
(O) -NR^Two-, (C_Five-C_Ten) -Arylene-C (O) -N
R^Two-, -O-, (C_Five-C_Ten) -Arylene-, -CO
-,-(C_Five-C_Ten) -Arylene-CO-, -NR^Two−,
-C (O) O-, -N = CR^Two-, -R^TwoC = N-or-
CR^Two= CR^Three[These radicals are
NR^TwoMay be replaced by and / or 1
Or 2 (C₁-C₆) -Replaced by alkanediyl
B is a single direct bond,
(C₁-C₆) -Alkanediyl, (C_Five-C₆) -Arile
, (C_Five-C₆) -Cycloalkanediyl, -C≡C-,
-NR^Two-C (O)-, -C (O) -NR^Two-, -NR^Two-S
(O)_Two-, -O- or -CR^Two= CR^Three-(These groups
Is one or two (C₁-C
₆) -Optionally substituted by alkanediyl]
D is a single direct bond, (C₁-C₆) -Alkandi
Ill, (C_Five-C₆) -Arylene, -O-, -NR^Two−,
-NR^Two-CO-, -NR^Two-C (O) -NR^Two-, -NR^Two
-C (S) -NR^Two-, -OC (O)-, -C (O)-, -S
(O)_Two-NR^Two-, -NR^Two-S (O)-, -NR^Two-S (O)
_Two-, -N = CR^Two-Or -R^TwoC = N- [these groups
Is one or two (C₁-C
₆) -Optionally substituted by alkanediyl]
E is a single direct bond, (C₁-C_Four) -Alkandi
Ill or (C_Two-C_Four) -Alkenediyl; F is
Single direct bond, (C₁-C₆) -Alkanediyl, -O
-, -CO-NR^Two-, -NR^Two-CO-, -NR^Two-C
(O) -NR^Two-, -OC (O)-, -C (O) O-, -CO
-, -S (O)_Two-, -S (O)_Two-NR^Two-, -NR^Two-S
(O)_Two-, -CR^Two= CR^Three-, -C≡C-, -N = CR^Two
-Or -R^TwoC = N- [these groups are
1 or 2 (C₁-C₆) -Arcandii
May be substituted with a group], and G isAnd L is C (R¹⁶) Or N; R⁰Is H,
(C₁-C₆) -Alkyl, (C_Three-C₆) -Cycloalkyl,
(C_Three-C₆) -Cycloalkyl- (C₁-C_Four) -Alkyl,
(C_Five-C_Ten) -Aryl, (C_Five-C _Ten) -Aryl- (C₁
-C_Four) -Alkyl, (C₁-C₆) -Alkyl-C (O)-,
(C_Five-C₆) -Cycloalkylmethyl-C (O)-, phenyl
-C (O) or benzyl-C (O) [wherein the alkyl group is 1 to
It may be substituted with 6 fluorine atoms].
R¹Is R^Two-C (= NR^Two) NR^Two-, R^TwoR^ThreeN-C (= N
R^Two)-,Embedded image(In the formula, Y'is NR^Two, O or S); R^Two
And R^ThreeBut independently of each other, H, and in some cases 1
To 1 or more than 1, preferably 1 to 6 fluorine
May be further substituted (C₁-C₆) -Alkyl, (C_Three
-C₆) -Cycloalkyl, (C_Three-C₆) -Cycloalkyl
-(C₁-C_Four) -Alkyl, (C_Five-C_Ten) -Aryl, (C
_Five-C_Ten) -Aryl- (C₁-C_Four) -Alkyl, H_TwoN,
R⁸OR⁹, R⁸-(C_Five-C_Ten) -Aryl-R⁹, R⁸NH
R⁹, R⁸R⁸NR⁹, R⁸NHC (O) R⁹, R⁸C (O)-,
H_TwoN-C (= NH) or H_TwoN-C (= NH) -NH-
Yes; R^Four, R^Five, R⁶And R⁷But independently of each other,
H, fluorine, OH, (C₁-C₆) -Alkyl, (C₆-C₁₂)
-Cycloalkyl, (C₆-C₁₂) -Cycloalkyl- (C
₁-C₆) -Alkyl or R⁸OR⁹, R⁸CO_TwoR⁹, R⁸
OC (O) R⁹, R⁸-(C_Five-C_Ten) -Aryl-R⁹, R⁸
NHR⁹, R⁸R⁸NR⁹, R⁸NHC (O) OR⁹, R⁸S
(O)_nNHR⁹, R⁸OC (O) NHR⁹, R⁸C (O) NH
R⁹, R⁸C (O) R⁹, R⁸NHC (O) NHR⁹, R⁸NHS
(O)_nNHR⁹, R⁸NHC (O) R⁹, R⁸NHS (O)_nR⁹
And R⁸But H, (C₁-C₆) -Alkyl, (C₆-C
₁₂) -Cycloalkyl, (C₆-C₁₂) -Cycloalkyl-
(C₁-C_Four) -Alkyl, (C_Five-C_Ten) -Aryl or
(C_Five-C_Ten) -Aryl- (C₁-C_Four) -Alkyl (ar
Kill group may be substituted by 1 to 6 fluorine atoms
Good]; R⁹Is a single direct bond or (C₁−
C₆) -Alkanediyl; R^TenBut C (O) R¹¹, S
(O)_nR¹¹Or P (O) R¹¹ _nAnd R¹¹But OH,
(C₁-C₆) -Alkoxy, (C_Five-C_Ten) -Aryl- (C
₁-C₆) -Alkoxy, (C_Five-C_Ten) -Aryloxy,
(C₁-C₆) -Alkylcarbonyloxy- (C₁-C_Four) −
Alkoxy, (C_Five-C_Ten) -Aryl- (C₁-C_Four) -A
Lucylcarbonyloxy- (C₁-C_Four) -Alkoxy, N
H_TwoOr mono- or di (C₁-C₆) -Alkylamino
And R¹², R¹³And R¹⁴But H, in some cases
Substituted with one or more than one fluorine
Good (C₁-C₆) -Alkyl, (C_Three-C₆) -Cycloalk
Le, (C_Three-C₆) -Cycloalkyl- (C₁-C_Four) -Arki
Le, (C_Five-C_Ten) -Aryl, (C_Five-C_Ten) -Aryl-
(C₁-C_Four) -Alkyl, H_TwoN, R⁸OR⁹, R⁸OC (O)
R⁹, R⁸-(C_Five-C_Ten) -Aryl-R⁹, R⁸R⁸N
R⁹, R⁸NHC (O) R⁹, R⁸C (O) NHR⁹, H_TwoN-C
(= NH)-, H_TwoN-C (= NH) -NH- or = O
Yes and group R¹²~ R¹⁴The two adjacent substitutions from
Together, -OCH_TwoO- or -OCH_TwoCH_Two
May be O-; R¹⁶However, depending on H, 1 to 6 fluorine
May be substituted (C₁-C₆) -Alkyl, (C_Three−
C₆) -Cycloalkyl, (C_Three-C₆) -Cycloalkyl-
(C₁-C_Four) -Alkyl, phenyl, phenyl- (C₁-C
_Four) -Alkyl or (C_Two-C₆) -Alkenyl; m
Is 3, 4 or 5; n is 1 or 2;
And p and q are 0 or 1 independently of each other.
A compound of formula I according to claim 1 or 2 and its physiology
Acceptable salt. 4. W is R ¹ -A-B-D-C (R ¹⁶ ) or R ¹ -A-B-D-CH = C; Y is C = O or C = S. Z is N (R ⁰ ); A is a single direct bond, (C ₁ -C ₄ ) -alkanediyl, —NR ^{2
-N = CR 2 -, - NR} 2 -C (O) -NR 2 -, - NR 2 -
C (O) O -, - NR 2 -S (O) n -, - NR 2 -S (O) n -
^{NR 2 -, - NR 2 -CO} -, - NR 2 - or -N = C
R ² [these radicals are in each case optionally substituted by NH and / or optionally by 1 or 2 (C ₁ -C ₄ ) -alkanediyl] Yes; B is a single direct bond, (C ₁ -C
₄ ) -Alkanediyl, phenylene, pyridine, divalent group of thiophene or furan, cyclohexanediyl,-
C≡C—, —CR ² ═CR ³ —, —C (O) —NR ² — or —NR ² —C (O) — [these radicals are in each case one or two (C ₁ -C ₄₎ - be a alkanediyl may be substituted by]; D is a single direct bond, (C ₁ -C ₄₎ - alkanediyl, phenylene,
^{-O -, - NR 2 -,} - NR 2 -C (O) -, - NR 2 -C
^{(O) -NR 2 -, -} R 2 N-S (O) 2 -NR 2 -, - NR 2
_{-S (O) 2 -, -} NR 2 -S (O) -, - N = CR 2 - or -R ² C = N-[these groups, in each case, one or two ( C ₁ -C ₄ ) -alkanediyl may be substituted]; E is a single direct bond or (C ₁ -C ₄ ) -alkanediyl; F
Is a single direct bond, (C ₁ -C ₆ ) -alkanediyl,
^{-O -, - CO-NR 2} -, - NR 2 -CO -, - NR 2
^{-C (O) -NR 2 -,} - S (O) 2 -NR 2 -, - NR 2 -S
(O) ₂ −, −CR ² = CR ³ −, −C≡C−, −N = CR ²
- or -R ² C = N-[these groups, one or two in each case (C ₁ -C ₄₎ - alkane may be substituted by diyl] be; G is [ Chemical 12] R ⁰ is H, (C ₁ -C ₆ ) -alkyl, trifluoromethyl, pentafluoroethyl, (C ₅ -C ₆ ) -cycloalkyl, (C ₅ -C ₆ ) -cycloalkyl- ( C ₁ -C ₂₎
-Alkyl, optionally substituted phenyl or benzyl, optionally substituted on a phenyl group; R ¹ is R ² R ³ NC (= NR ² ), Embedded image Where Y'is NH, O or S; R ²
And R ³ , independently of one another, are H, (C ₁ -C ₆ ) -alkyl, trefluoromethyl, pentafluoroethyl,
(C ₅ -C ₆₎ - cycloalkyl, (C ₅ -C ₆₎ - cycloalkyl - (C ₁ -C ₂₎ - alkyl, phenyl, benzyl, H
_{^{2 N, R 8 OR 9,}} R 8 - (C 5 -C 10) - aryl -R ^9, R
⁸ NHR ⁹ , R ⁸ R ⁸ NR ⁹ , R ⁸ NHC (O) R ⁹ , H ₂ N-C
(= NH) or _{H 2 C-C (= NH} ) -NH- and have;
R ⁴ , R ⁵ , R ⁶ and R ⁷ , independently of one another, are H, fluorine, OH, (C ₁ -C ₆ ) -alkyl, (C ₁₀ -C ₁₂ ) -cycloalkyl, (C _10- ). C ₁₂₎ - cycloalkyl - (C ₁ -C
₆₎ - alkyl or ^{R 8 OR 9, R 8 -} (C 5 -C 10) - aryl ^{-R 9, R 8 R 8 NR} 9, R 8 NHC (O) OR 9, R 8 S
(O) _n NHR ⁹ , R ⁸ OC (O) NHR ⁹ or R ⁸ C (O) N
HR ⁹ ; R ⁸ is H, (C ₁ -C ₆ ) -alkyl, (C
₁₀ -C ₁₂₎ - cycloalkyl, (C ₁₀ -C ₁₂₎ - cycloalkyl - (C ₁ -C ₂₎ - alkyl, (C ₅ -C ₁₀₎ aryl or (C ₅ -C ₁₀₎ - aryl - ( C ₁ -C ₂ ) -alkyl; R ⁹ is a single direct bond or (C ₁ -C ₆ )-
Alkanediyl; R ¹⁰ is C (O) R ¹¹ ; R
¹¹ is OH, (C ₁ -C ₆ ) -alkoxy, phenoxy, benzyloxy, (C ₁ -C ₄ ) -alkylcarbonyloxy- (C ₁ -C ₄ ) -alkoxy, NH ₂ , mono- or di ( C
₁ -C ₆ - alkyl) an amino; R ¹⁶ is, H, (C ₁ -
C ₄ ) -Alkyl, trifluoromethyl, pentafluoroethyl, (C ₅ -C ₆ ) -cycloalkyl, (C ₅ -C ₆ ) -cycloalkyl- (C ₁ -C ₂ ) -alkyl, phenyl or benzyl 1; n is 1 or 2; and p and q are 0 or 1 independently of one another.
A compound of formula I according to any of paragraph 3 and its physiologically acceptable salts. 5. A process for the preparation of a compound of formula I as claimed in any one of claims 1 to 4 which comprises coupling two or more flalagments which can be derivatized reverse synthetically from formula I. . 6. Use of a compound of formula I according to any of claims 1 to 4 as a medicament. 7. Nephropathy and retinopathy for the treatment and prevention of cardiovascular diseases, as inhibitors of bone resorption by osteoclasts, as inhibitors of tumor growth and metastasis, as anti-inflammatory agents. 5. A vitronectin receptor antagonist for the treatment and prophylaxis of and as a vitronectin receptor antagonist for the treatment and prevention of diseases based on the interaction between vitronectin receptor and ligand in cell-cell or cell-matrix interaction processes. Use of a compound of formula I according to any of the paragraphs. 8. A compound of formula I or a physiologically acceptable salt thereof according to any one of claims 1 to 4, in addition to pharmaceutically acceptable carrier substances and additives. A pharmaceutical preparation containing